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.

Inhibitory Control Training and iTBS for Excess Weight: Behavioral and Brain Changes (InhibE).

Overweight and Obesity

Inhibition, Psychological

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 study the effectiveness of iTBS in left DLPFC
     alone and in combination with inhibitory control training for the treatment of EW.

     Objective 2: To characterize the effects of neuromodulation with iTBS of left 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 3: To determine the relationship of biological parameters 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 4: To analyse the economic evaluation of the cost-effectiveness and
     cost-utility of combined inhibitory control training and neuromodulation with iTBS
     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. To do so, it will be relied on the only study to date that has analyzed
     changes in BMI in people with obesity after the administration of 4 rTMS sessions
     over 2 weeks, which found a small effect size (Cohen&#39;s d= 0.31; Kim et al.,
     2018). Thus, considering a small effect size for conducting ANOVAs (f= 0.15), the
     minimum recommended sample size to reach a power of 0.90 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 39 participants
     per group. Although there is no previous study in which inhibitory control training
     and iTBS have been applied together, it is hypothesized that their results will be
     superior to those of the separate techniques. However, it is considered that the
     comparison between the application of the combined intervention and neuromodulation
     alone will result in a very small effect size. Thus, the n of the groups will be
     increased to 45.

     Participants (N=135) will be randomly allocated to three groups: (i) group 1
     (combined intervention: active stimulation of the DLPFC with iTBS and inhibitory
     control training) n=45; (ii) group 2 (active stimulation of the DLPFC with iTBS)
     n=45; group 3 (control group of sham iTBS) n=45.

     2.3. Interventions

     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.

iTBS of the left DLPFC

iTBS of the vertex

Inhibitory control training

Inhibitory Control Training and Theta Burst Transcranial Magnetic Stimulation (iTBS) for Treating People With Excess Weight: Behavioral and Brain Changes (InhibE).

Change in BMI: Weight and height will be combined to report BMI in kg/m^2. Weight will be
obtained in kilograms with a digital scale (TANITA Corporation of America) and height in
meters with a measuring rod (SECA Tape Measure 206).

Food Go/No-go task (Based on the FoodTrainer App; Lawrence et al., 2015): Pictures appear
and afterwards a green (Go signal) or red (No-Go signal) circle appears around them.
Participants are instructed to score points by answering with a knob if the image is
surrounded by a green circle, but not to press when the image is surrounded by a red
circle. The presentation of the images is the same as in the FoodTrainer application: 50%
of the images are food, with 100% of the healthy ones being presented under the 'Go'
condition and 100% of the unhealthy ones under the 'No-Go' condition. The remaining 50%
are non-food images, with 50-50% paired with 'Go' and 'No-Go' cues. In addition,
participants can choose which categories of unhealthy foods they want to train. Brain
activation to Go vs. No-Go stimuli and food vs. non-food stimuli will be compared. The
task will be analysed to assess the brain activity associated with the task, using a
psychophysiological interaction analysis(PPI).

Principal Investigator

The Neveu et al. (2018) task will be used, which 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).

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.

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.

To take these measurements at home, participants should ask someone for help and follow
our instructions. WC will be measured in cm with a tape around the waist, just above the
navel.

To take these measurements at home, participants should ask someone for help and follow
our instructions. WHR results from WC divided by the hip circumference in cm (tape placed
at the maximum prominence of the buttocks).

To take these measurements at home, participants should ask someone for help and follow
our instructions. WHtR results from WC divided by the height measured standing with heels
close together and trunk erect.

Change in Food Craving. Food Craving Questionnaire State-reduced (FCQ-S-r)consists of 15
items to be scored on a 5-point scale ranging from strongly disagree to strongly agree. A
higher score indicates higher state of craving at the time of the assessment

Diet information during the last year (pre-treatment), two last weeks (post-treatment)
and 3 last months (follow-up) will be collected through a 52-item Food frequency
questionnaire (CFA). Participants must record quantities of all the foods and drinks
consumed during those periods. Data are transformed into total calories and calories from
fats, carbohydrates, and sugars

International Physical Activity Questionnaire (IPAQ; www.ipaq.ki.se): is a questionnaire
with 7 questions on physical activity during the last week, as well as walking and
sitting time.It evaluates physical activity related to work, activity at home and free
time determines the degrees of activity based on the metabolic equivalents (MET)
consumed.Higher scores indicate greater physical activity

Beck Depression Inventory will be administered to test depression symptoms.The scores
range from 0 to 63 points. The higher the score, the greater the severity of depressive
symptoms

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

Dutch Eating Behaviour Questionnaire (DEBQ) 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).

Reward-Based Eating Scale (RED) is a 13 items questionnaire that evaluates worries about
foods, losing intake control and absence of satiety. Higher scores reflect higher
reward-based eating drive.

Coping subscale of the Palatable Eating Motives Scale (PEMS) 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.

The Emotion Questionnaire (ERQ) consists of 10 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).

Motor inhibition will be assessed using FoodT. 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.

Using a Stroop task with food, the interference of food-related words on task performance
can be measured as an assessment of cognitive inhibition.

Score on the Food Delay Discounting will be used to measure the sensitivity to immediate
rewards vs higher value rewards delayed. The participant&#39;s 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.

This will be assessed using the Punishment Sensitivity and Reward Sensitivity
Questionnaire (PSRSQ) of 48 items. Responses in the scale are in a &#34;yes/no&#34;
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.

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

Working Memory 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.

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

Iowa Gambling Task will be used to assess decision-making using money rewards.

Experimental: Active iTBS of the DLPFC combined with inhibitory control training. An
experimental group will receive: i) an informative session; ii) 4 pre treatment sessions
(one assessment session with questionnaires, one with fMRI and one with biological
samples. Also, a counselling session on diet and on physical exercise); iii) participate
in 2 weekly individual intervention sessions that consist of iTBS of the left DLPFC (10
min) followed immediately by inhibitory control training for 10 minutes; iv) 3 sessions
of post treatment assessment (one with questionnaires, one with fMRI and one with
biological samples); v) 2 follow-up assessment sessions (3 months after completing the
intervention) to repeat questionnaires and biological samples

Experimental: Active iTBS of the DLPFC only. An experimental group will receive: i) an
informative session; ii) 4 pre treatment sessions (one assessment session with
questionnaires, one with fMRI and one with biological samples. Also, a counselling
session on diet and on physical exercise); iii) participate in 2 weekly individual
intervention sessions that consist of iTBS of the left DLPFC that will last about 10
minutes each; iv) 3 sessions of post treatment assessment (one with questionnaires, one
with fMRI and one with biological samples); v) 2 follow-up assessment sessions (3 months
after completing the intervention) to repeat questionnaires and biological samples

Control: iTBS of the vertex (sham). The control group will receive: i) an informative
session; ii) 4 pre treatment sessions (one assessment session with questionnaires, one
with fMRI and one with biological samples. Also, a counselling session on diet and on
physical exercise); iii) participate in 2 weekly individual intervention sessions that
consist of iTBS of the vertex that will last about 10 minutes each; iv) 3 sessions of
post treatment assessment (one with questionnaires, one with fMRI and one with biological
samples); v) 2 follow-up assessment sessions (3 months after completing the intervention)
to repeat questionnaires and biological samples

Inhibitory Control Training and iTBS for Excess Weight: Behavioral and Brain Changes (InhibE).

About this trial

Study ID

Status

Type

Phase

Placebo

Accepting

Trial Timing

What is this trial about?

What are the participation requirements?