Clinical trial NCT06668077: Inhibitory Control Training and iTBS for Excess Weight: Behavioral and Brain Changes (InhibE).
Official title: Inhibitory Control Training and Theta Burst Transcranial Magnetic Stimulation (iTBS) for Treating People With Excess Weight: Behavioral and Brain Changes (InhibE).
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Overweight and Obesity
Inhibition, Psychological
Keywords: excess weight
overweight
inhibitory control
cognitive training
iTBS
Lead sponsor: Universidad de Granada
Sponsor class: OTHER
Collaborators: name: Government of Spain
First posted: 2024-10-31
Enrollment: 141
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Parallel group randomized controlled trial
Primary purpose: TREATMENT

Brief summary: People with excess weight (EW) 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 the brain level, to alterations in the activation of areas such as the dorsolateral prefrontal cortex (DLPFC) and its connectivity. The proposed intervention seeks to target these issues. Thus, the present study aims to characterize the effects of neuromodulation with intermittent theta burst transcranial magnetic stimulation (iTBS) of the DLPFC alone and in combination with inhibitory control training to produce brain, cognitive and behavioral changes, and modify altered biological parameters in people with EW. Participants will be randomly allocated to one of three groups: (1) a group that will receive active iTBS of the DLPFC combined with inhibitory control training with a food Go/No-go paradigm, (2) a group that will receive active iTBS of the DLPFC only, and (3) a control group that will receive sham iTBS. It is hypothesized that the combined intervention will obtain better results that the neuromodulation alone, and that both interventions, compared to sham iTBS, will achieve: (i) decreased body mass index, (ii) decreased craving, (iii) modified brain connectivity and activation both at rest and linked to task performance with food stimuli, (iv) improved anthropometric measures (waist circumference and waist-to-hip and waist-to-height ratios), (v) improved eating and exercise behaviors (decreased caloric intake and increased frequency and time of physical activity), (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.

Detailed description: 1. STARTING HYPOTHESES AND GENERAL OBJECTIVE HYPOTHESIS:

   HYPOTHESIS: Neuromodulation with iTBS applied to the left DLPFC in combination with inhibitory control training with a food Go/No-go paradigm will be associated with decreased (i) BMI, and (ii) craving; (iii) modified brain connectivity and activation both at rest and linked to task performance with food stimuli; improved (iv) anthropometric measures (waist circumference and waist-to-hip and waist-to-height ratios), (v) eating and exercise behaviors (caloric intake increased frequency and time of physical activity), (vi) emotional symptoms and emotional eating (depression, anxiety, emotional regulation, emotional eating, reward-related eating, non-homeostatic eating), (vii) cognitive abilities (motor and cognitive inhibition, delay of gratification, impulsivity, working memory, cognitive flexibility and decision making); (viii) changes in biological parameters (plasma 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 alone and in combination with inhibitory control training to generate brain, behavioural, emotional, cognitive and biological changes in people with EW.

   1.1. Specific Aims: Objective 1: To determine the effectiveness of iTBS of the DLPFC as an add-on to the treatment as usual (TAU: diet and exercise) for the treatment of people with excess weight (improvements in BMI, craving, anthropometric measures, food and exercise behaviours, emotional symptoms and emotional eating, cognitive measures and biological parameters).

   Objective 2: To study the effectiveness of combining iTBS and inhibitory control training compared to iTBS alone (both as an add-on to TAU), for the treatment of EW (using the same parameters before) Objective 3: To characterize the effects of neuromodulation with iTBS of DLPFC alone and 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 4: 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 and connectivity).

   Objective 5: To analyse the economic evaluation of the cost-effectiveness and cost-utility of combined training (neuromodulation with iTBS and inhibitory control training) in people with EW, and to analyse the budgetary impact of the program if it were to be implemented in the national health system.
2. METHODOLOGY 2.1. Design: Randomized controlled trial of parallel groups. 2.2. Sample size and statistical power: The sample size was calculated using the G\*Power 3.1 tool G-Power v3.1.9.7. To do so, we relied on the only study to date that has analysed changes in BMI in people with obesity after the administration of 4 rTMS sessions over 2 weeks, which found a small effect size (Cohen's d= 0.31). Thus, considering a small effect size for conducting ANOVAs (f= 0.15), the minimum recommended sample size to reach a power of 0.95 and alpha level of 0.05 to calculate the interaction model of the three groups (combined intervention vs. neuromodulation alone vs. sham iTBS) and three repeated measures was 141 (47 participants per group).

   Pre-treatment sessions: information, dietary plus physical guidelines (all groups):

   All participants will participate in a group briefing informational session about the procedure and rationale of the study that will last about an hour. Also, informative videos and brochures will be provided. After that, there will be two 90-minute sessions given by a nutritionist and personal trainer respectively to provide individualized diet and physical exercise instructions.

   Neurocognitive intervention:

   Duration: 2 weeks of 5 daily sessions. Part 1 (all groups). Three minutes of neuromodulation with iTBS (in the DLPFC for groups 1 and 2; in the vertex for group 3). The whole process of iTBS includes 3 minutes of stimulation and time devoted to coil location, reception and farewell (10 minutes).

   Part 2 (group 1). Immediately after the iTBS, only group 1 will also receive a 10-minute inhibition training with the FoodT app in their smart phones.

   In this task, participants are instructed to touch green circled items as quickly as possible, but to withhold their response and not to press on the red circled items. Some images are food (high-calorie and low-calorie), some non-foods. Participants can choose which food categories would like to train to resist, and those high-calorie foods are always paired with the no-go signal.
3. PROCEDURE Assessments will be delivered online through LimeSurvey and Milliseconds platforms. Inclusion and exclusion criteria will be checked.

All candidates who meet the criteria will attend an information meeting to receive written and oral information about the project 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 three assessments (pre, post, 3-month follow-up). What will differentiate the groups will be, therefore, the treatment: iTBS applied to the DLPFC followed by inhibitory control training vs. iTBS applied to the DLPFC vs. iTBS applied to the vertex (sham). At the end of the project, if an intervention is effective, the other groups will be offered the possibility of receiving it.

Informative and evaluation sessions will be developed in groups of 4-6 people. 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 8 experimental groups of DLPFC neuromodulation combined with inhibitory control training (45 participants), 8 experimental groups of DLPFC neuromodulation alone (45 participants) and 8 control groups of sham iTBS (45 participants). The program will comprise 6 weeks including: three assessments (pre, post, and 3-month follow-up), ten intervention sessions (two weeks of 5 daily sessions), information and the diet and exercise sessions too. Assessment sessions will last about 2 hours while intervention sessions will between 10 and 20 minutes depending on the group. The contents of each of the sessions will be as follows:

1. Informative session (session 1; week 1): For the participants to understand the foundation of the intervention information about the aims, basis of the project and the procedure of the research will be given. 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, 3 and 4; week 2): All participants will complete, in session 2, 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, IPAQ, DASS-21, BDI-II, PEMS, RED, DEBQ, PSRSQ, ERQ, UPPS-P, SF-36, SOCRATES 00, QEWP-5, sociodemographic questionnaire, another one about used health resources, stigma and previous treatments questions. Also, all participants will undergo the fMRI session (session 3) and biological sample collection (blood, saliva, feces and urine) and anthropometric measures to calculate BMI, WC, WHR and WHtR (session 4).
3. Nutrition and physical exercise session (session 5; week 3): Participants will receive information on healthy nutritional (Ph.D. Nutritionist) and physical exercise (Ph.D. Sports Science) habits. In addition, participants will receive individualized diet and physical exercise guidelines, and participants will be able to consult any doubts to both professionals through WhatsApp groups.
4. Intervention sessions (sessions 6 to 15; weeks 4 and 5): Intervention will consist of five weekly individual sessions for two weeks, with a 10-20-minute total duration each. The stimulation parameters are based on the protocols for the application of iTBS in people with food intake problems, by Barone et al., (2023), and following international safety recommendations. The procedure in the three groups consists of:

   A. 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 group it will be the left DLPFC area (x -37, y -34, z 78) corresponding to F3 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.

   B. Neuromodulation applying an intermittent TBS with Megastim Rapid 2 magnetic stimulator and figure-8-coil: 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\&#39;s maximum output.

   C. Cognitive inhibitory control training (10 minutes): It will be performed with the FoodT app, for 10 minutes and will be applied immediately after the iTBS, taking advantage of its time of maximum brain potentiation. In this app, 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 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 with the no-go signal.
5. Post-treatment assessment (session 16; week 6): 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, IPAQ, DASS-21, BDI-II, PEMS, RED, DEBQ, PSRSQ, ERQ, UPPS-P, SF-36 and a questionnaire about used health resources. Also, fMRI and biological samples of the pre-treatment assessment will be repeated.
6. Follow-up assessment (sessions 17; week 18): Follow-up at 3 months after the intervention will include the following measures: WCST, Food Go/NoGo, IGT, Stroop, Food DD, N-Back, CFA, IPAQ, DASS-21, BDI-II, PEMS, RED, DEBQ, PSRSQ, ERQ, UPPS-P, SF-36, sociodemographic questionnaire and another one about used health resources, and collection of biological samples and anthropometric measures to obtain the main and secondary outcome measures.

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

Eligibility criteria: Inclusion Criteria:

* BMI between 25 and 39.9
* Age between 18 and 60 years
* 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
* Severe psychopathological disorders and suicidal ideation or treatment for depression
* Eating disorders
* Contraindication for performing fMRI (pregnancy, metal implants, etc.) or iTBS (tinnitus, dizziness, surgical interventions, diseases or drugs that affect the CNS, etc.)

Primary outcomes:
measure: Body Mass Index (BMI)
timeFrame: Pre-treatment assessment (week 2), post-treatment assessment (week 6) and follow-up (week 18)
measure: Changes in brain activation during a inhibitory control task (neuroimaging measures)
timeFrame: Pre-treatment assessment (week 2) and post-treatment assessment (week 6)
Secondary outcomes:
measure: Changes in Food decision-making (neuroimaging measures)
timeFrame: Pre-treatment assessment (week 2) and post-treatment assessment (week 6)
measure: Changes in Brain connectivity at rest (neuroimaging measures)
timeFrame: Pre-treatment assessment (week 2) and post-treatment assessment (week 6)
measure: Changes in White matter integrity (neuroimaging measures)
timeFrame: Pre-treatment assessment (week 2) and post-treatment assessment (week 6)
measure: Waist-to-height ratio (WHtR). Mean change from baseline at post-intervention
timeFrame: Pre-treatment assessment (week 2), post-treatment assessment (week 6) and follow-up (week 18)
measure: Food Craving. Mean change from baseline at post-intervention
timeFrame: Pre-treatment assessment (week 2), post-treatment assessment (week 6) and follow-up (week 18)
measure: Eating behaviour. Mean change from baseline at post-intervention
timeFrame: Pre-treatment assessment (week 2), post-treatment assessment (week 6) and follow-up (week 18)
measure: Physical activity behaviour. Mean change from baseline at post-intervention
timeFrame: Pre-treatment assessment (week 2), post-treatment assessment (week 6) and follow-up (week 18)
measure: Exercise adherence. Mean change from baseline at post-intervention
timeFrame: Pre-treatment assessment (week 2), post-treatment assessment (week 6) and follow-up (week 18)
measure: Adherence to diet. Mean change from baseline at post-intervention
timeFrame: Pre-treatment assessment (week 2), post-treatment assessment (week 6) and follow-up (week 18)
measure: Depression symptoms. Mean change from baseline at post-intervention
timeFrame: Pre-treatment assessment (week 2), post-treatment assessment (week 6) and follow-up (week 18)
measure: Anxiety and Stress. Mean change from baseline at post-intervention
timeFrame: Pre-treatment assessment (week 2), post-treatment assessment (week 6) and follow-up (week 18)
measure: Non homeostatic eating. Mean change from baseline at post-intervention
timeFrame: Pre-treatment assessment (week 2), post-treatment assessment (week 6) and follow-up (week 18)
measure: Reward-related eating. Mean change from baseline at post-intervention
timeFrame: Pre-treatment assessment (week 2), post-treatment assessment (week 6) and follow-up (week 18)
measure: Emotional eating. Mean change from baseline at post-intervention
timeFrame: Pre-treatment assessment (week 2), post-treatment assessment (week 6) and follow-up (week 18)
measure: Emotion Regulation Strategies. Mean change from baseline at post-intervention
timeFrame: Pre-treatment assessment (week 2), post-treatment assessment (week 6) and follow-up (week 18)
measure: Motor inhibition. Mean change from baseline at post-intervention
timeFrame: Pre-treatment assessment (week 2), post-treatment assessment (week 6) and follow-up (week 18)
measure: Cognitive inhibition. Mean change from baseline at post-intervention
timeFrame: Pre-treatment assessment (week 2), post-treatment assessment (week 6) and follow-up (week 18)
measure: Delay of gratification. Mean change from baseline at post-intervention
timeFrame: Pre-treatment assessment (week 2), post-treatment assessment (week 6) and follow-up (week 18)
measure: Inhibition and activation systems. Mean change from baseline at post-intervention
timeFrame: Pre-treatment assessment (week 2), post-treatment assessment (week 6) and follow-up (week 18)
measure: Self-reported impulsivity. Mean change from baseline at post-intervention
timeFrame: Pre-treatment assessment (week 2), post-treatment assessment (week 6) and follow-up (week 18)
measure: Working Memory. Mean change from baseline at post-intervention
timeFrame: Pre-treatment assessment (week 2), post-treatment assessment (week 6) and follow-up (week 18)
measure: Cognitive flexibility. Mean change from baseline at post-intervention
timeFrame: Pre-treatment assessment (week 2), post-treatment assessment (week 6) and follow-up (week 18)
measure: Decision making. Mean change from baseline at post-intervention
timeFrame: Pre-treatment assessment (week 2), post-treatment assessment (week 6) and follow-up (week 18)
Other outcomes:
measure: Descriptive measures
timeFrame: Pre-treatment assessment (week 2)
measure: Depression Symptoms. Screening
timeFrame: Pre-treatment assessment (week 2)
measure: Anxiety Symptoms. Screening
timeFrame: Pre-treatment assessment (week 2)
measure: Eating and Weight Patterns. Screening
timeFrame: Pre-treatment assessment (week 2)
measure: Using of Health Resources
timeFrame: Pre-treatment assessment (week 2), post-treatment assessment (week 6) and follow-up (week 18)
measure: Motivation to change
timeFrame: Pre-treatment assessment (week 2)
measure: Stigma
timeFrame: Pre-treatment assessment (week 2)
measure: Previous treatment history
timeFrame: Pre-treatment assessment (week 2)
measure: Hormone levels (Biological samples collection)
timeFrame: Pre-treatment assessment (week 2), post-treatment assessment (week 6) and follow-up (week 18)
measure: Glucose and triglycerides levels (Biological samples collection)
timeFrame: Pre-treatment assessment (week 2), post-treatment assessment (week 6) and follow-up (week 18)
measure: Insulin levels (Biological samples collection)
timeFrame: Pre-treatment assessment (week 2), post-treatment assessment (week 6) and follow-up (week 18)
measure: Inflammatory parameters (Biological samples collection)
timeFrame: Pre-treatment assessment (week 2), post-treatment assessment (week 6) and follow-up (week 18)
measure: Satiety markers (Biological samples collection)
timeFrame: Pre-treatment assessment (week 2), post-treatment assessment (week 6) and follow-up (week 18)
measure: Genetic analyses (Biological samples collection)
timeFrame: Pre-treatment assessment (week 2), post-treatment assessment (week 6) and follow-up (week 18)
measure: Oral microbiota (Biological samples collection)
timeFrame: Pre-treatment assessment (week 2), post-treatment assessment (week 6) and follow-up (week 18)
measure: Gut microbiota (Biological samples collection)
timeFrame: Pre-treatment assessment (week 2), post-treatment assessment (week 6) and follow-up (week 18)
measure: Proteomics analysis. (Biological samples collection)
timeFrame: Pre-treatment assessment (week 2), post-treatment assessment (week 6) and follow-up (week 18)
measure: Quality of Life (Measures to calculate cost effectiveness, cost utility and budget impact analyses)
timeFrame: Pre-treatment assessment (week 2), post-treatment assessment (week 6) and follow-up (week 18)
measure: Years of Life Adjusted for Quality (Measures to calculate cost effectiveness, cost utility and budget impact analyses)
timeFrame: Pre-treatment assessment (week 2), post-treatment assessment (week 6) and follow-up (week 18)
measure: BMI (Measures to calculate cost effectiveness, cost utility and budget impact analyses)
timeFrame: Pre-treatment assessment (week 2), post-treatment assessment (week 6) and follow-up (week 18)
measure: Intensity of Food Craving (Measures to calculate cost effectiveness, cost utility and budget impact analyses)
timeFrame: Pre-treatment assessment (week 2), post-treatment assessment (week 6) and follow-up (week 18)
measure: Health Resource Costs (Measures to calculate cost effectiveness, cost utility and budget impact analyses)
timeFrame: Pre-treatment assessment (week 2), post-treatment assessment (week 6) and follow-up (week 18)
measure: iTBS Session Staff Time (Measures to calculate cost effectiveness, cost utility and budget impact analyses)
timeFrame: Pre-treatment assessment (week 2), post-treatment assessment (week 6) and follow-up (week 18)
measure: Inhibitory Control Training Session Staff Time (Measures to calculate cost effectiveness, cost utility and budget impact analyses)
timeFrame: Pre-treatment assessment (week 2), post-treatment assessment (week 6) and follow-up (week 18)
measure: Equipment Costs (Measures to calculate cost effectiveness, cost utility and budget impact analyses)
timeFrame: Pre-treatment assessment (week 2), post-treatment assessment (week 6) and follow-up (week 18)
Locations:
city: Granada
country: Spain
facility: Mind, Brain and Behavior Research Center at University of Granada (CIMCYCUGR)
Study officials:
affiliation: Universidad de Granada
name: Raquel Vilar López, Ph.D.
role: PRINCIPAL_INVESTIGATOR
References: