Transcranial Magnetic Stimulation (TMS) in Obesity

Study Overview
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Brief Summary
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Obesity is a metabolic disease that has reached epidemic proportions. Insofar no long-term effective drug treatment was developed for obesity. Lyfe style modulation and bariatric surgery are the only interventions with a limited rate of success. Obesity is due to several factors, mainly linked to a neurophysiological mechanism of food addiction. The use of repetitive deep Transcranial Magnetic Stimulation (dTMS) was proposed to reduce appetite and food craving in obese subjects, leading eventually to a weight reduction. dTMS was already tested successfully in other forms of addiction (smoking, alcohol, cocaine) and the usefulness of dTMS in the treatment of food addiction, and therefore in obesity, was hypothesized. End-points of this research will be: 1) effect on food craving; 2) acute and chronic effects on blood level of hormones acting on the appetite regulation; 3) chronic effects on body weight. The demonstration that a safe, non-invasive and repeatable methodology can treat obesity reducing food craving and modulating appetite/satiety hormones secretion will constitute a cornerstone in translational medicine of metabolic diseases.

Official Title
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Impact of Deep Transcranial Magnetic Stimulation (dTMS) on Satiety and Weight Control

Conditions
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Obesity, Food Craving, Appetite and General Nutritional Disorders

Intervention / Treatment
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* Device: High frequency repetitive dTMS
* Device: Low frequency repetitive dTMS
* Device: Sham


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age: 22-65 years If the patient is taking medications, it must take on a stable dose for at least a month Obesity: ≤ 30 BMI ≤ 45 Ability to follow verbal or written instructions. Exclusion Criteria: Axis-I and II psychiatric disorders according to DSM criteria 5 (such as Major Depression, Bipolar Disorder, or Attention Deficit Disorder) IQ score < 85 Organic brain disorders: history of stroke, brain major surgery or head trauma Pregnancy or lactation, absence of medically approved contraceptive methods in females of childbearing potential Serious or poorly controlled diseases (hepatic, renal or hearth failure, atrial fibrillation or other heart rhythm disorders) H yperglycemia - Fasting glucose level > 170 mg/dl Urine drug screen positive for amphetamines, barbiturates, cannabinoids, cocaine metabolites, opiates and phencyclidine Positivity to blood alcohol test Metal in any part of the head, except for dental fillings Implanted infusion pumps Intracardiac devices (pacemakers, heart valves ...) History of diseases whose exacerbation could be fatal (e.g. cardiovascular disease, increased intracranial pressure) History of epilepsy or a family history of epilepsy among first-degree relatives Medications associated with lowered seizure threshold (such as antidepressants, anxiolytics…) Treatment with anti-obesity medications or other medications influencing body weight within 3 month prior to Screening Visit Starting a weight loss plan at any time during data collection for the subject Patients affected by galactosemia, priapism and terminal illness Patients on fluid restriction for SIADH or other conditions Contraindications to perform the Magnetic Resonance Imaging (MRI).

Ages Eligible for Study
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Minimum Age: 22 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: High frequency repetitive dTMS + Cue<br>10 obese individuals fulfilling all inclusion/exclusion criteria for the study will be randomized to active high frequency repetitive dTMS treatment with cue. Stimulation will be performed 3 times per week, for 5 weeks (15 treatments). In this group, stimulation will be performed with the following features: Intensity of stimulation: 120% of the resting Motor Threshold (rMT), Frequency: 18 Hz, Duration of the train: 2 sec, Inter-train interval: 20 sec, Trains number: 80, Total pulses: 2880, Total treatment duration: 29.3 min, Cue (sight of food preferred by patient): present. | Device: High frequency repetitive dTMS<br>* Focal rTMS will be performed using a Magstim Rapid2 magnetic stimulator (The Magstim Co. Ltd., U.K.) equipped with an H-shaped coil. The used H-coil version is the H-addiction specifically designed to stimulate the insula and the Pre-Frontal Cortex (PFC). This novel H-coil allows direct stimulation of deeper brain regions, like insula (3 cm vs 1.5 cm from the skull). Before each stimulation the resting Motor Threshold (rMT) should be determined. The rMT will be determined over the left primary motor cortex, afterwards the coil will be moved forward 6 cm anterior the motor spot and aligned symmetrically over the PFC and insula. Repetitive dTMS induces long-lasting changes in neural excitability and dopamine release, specifically high-frequency rTMS (18 Hz) enhances cortical excitability.<br>|
| Experimental: High frequency repetitive dTMS - No Cue<br>10 obese individuals fulfilling all inclusion/exclusion criteria for the study will be randomized to active high frequency repetitive dTMS treatment without cue. Stimulation will be performed 3 times per week, for 5 weeks (15 treatments). In this group, stimulation will be performed with the following features: Intensity of stimulation: 120% of the resting Motor Threshold (rMT), Frequency: 18 Hz, Duration of the train: 2 sec, Inter-train interval: 20 sec, Trains number: 80, Total pulses: 2880, Total treatment duration: 29.3 min, Cue (sight of food preferred by patient): absent. | Device: High frequency repetitive dTMS<br>* Focal rTMS will be performed using a Magstim Rapid2 magnetic stimulator (The Magstim Co. Ltd., U.K.) equipped with an H-shaped coil. The used H-coil version is the H-addiction specifically designed to stimulate the insula and the Pre-Frontal Cortex (PFC). This novel H-coil allows direct stimulation of deeper brain regions, like insula (3 cm vs 1.5 cm from the skull). Before each stimulation the resting Motor Threshold (rMT) should be determined. The rMT will be determined over the left primary motor cortex, afterwards the coil will be moved forward 6 cm anterior the motor spot and aligned symmetrically over the PFC and insula. Repetitive dTMS induces long-lasting changes in neural excitability and dopamine release, specifically high-frequency rTMS (18 Hz) enhances cortical excitability.<br>|
| Experimental: Low frequency repetitive dTMS+ Cue<br>10 obese individuals fulfilling all inclusion/exclusion criteria for the study will be randomized to active low frequency repetitive dTMS treatment with cue. Stimulation will be performed 3 times per week, for 5 weeks (15 treatments). In this group, stimulation will be performed with the following features: Intensity of stimulation: 120% of the resting Motor Threshold (rMT) Frequency: 1 Hz Duration of the train: 10 min Inter-train interval: 1 min Trains number: 4 Total pulses: 2400 Total treatment duration: 43 min Cue (sight of food preferred by patient): present | Device: Low frequency repetitive dTMS<br>* Focal rTMS will be performed using a Magstim Rapid2 magnetic stimulator (The Magstim Co. Ltd., U.K.) equipped with an H-shaped coil. The used H-coil version is the H-addiction specifically designed to stimulate the insula and the Pre-Frontal Cortex (PFC). This novel H-coil allows direct stimulation of deeper brain regions, like insula (3 cm vs 1.5 cm from the skull). Before each stimulation the resting Motor Threshold (rMT) should be determined. The rMT will be determined over the left primary motor cortex, afterwards the coil will be moved forward 6 cm anterior the motor spot and aligned symmetrically over the PFC and insula. Repetitive dTMS induces long-lasting changes in neural excitability and dopamine release, specifically low-frequency rTMS (1 Hz) inhibits cortical excitability.<br>|
| Experimental: Low frequency repetitive dTMS - No Cue<br>10 obese individuals fulfilling all inclusion/exclusion criteria for the study will be randomized to active low frequency repetitive dTMS treatment without cue. Stimulation will be performed 3 times per week, for 5 weeks (15 treatments). In this group, stimulation will be performed with the following features: Intensity of stimulation: 120% of the resting Motor Threshold (rMT), Frequency: 1 Hz, Duration of the train: 10 min, Inter-train interval: 1 min, Trains number: 4, Total pulses: 2400, Total treatment duration: 43 min, Cue (sight of food preferred by patient): absent. | Device: Low frequency repetitive dTMS<br>* Focal rTMS will be performed using a Magstim Rapid2 magnetic stimulator (The Magstim Co. Ltd., U.K.) equipped with an H-shaped coil. The used H-coil version is the H-addiction specifically designed to stimulate the insula and the Pre-Frontal Cortex (PFC). This novel H-coil allows direct stimulation of deeper brain regions, like insula (3 cm vs 1.5 cm from the skull). Before each stimulation the resting Motor Threshold (rMT) should be determined. The rMT will be determined over the left primary motor cortex, afterwards the coil will be moved forward 6 cm anterior the motor spot and aligned symmetrically over the PFC and insula. Repetitive dTMS induces long-lasting changes in neural excitability and dopamine release, specifically low-frequency rTMS (1 Hz) inhibits cortical excitability.<br>|
| Sham Comparator: Sham<br>10 obese individuals fulfilling all inclusion/exclusion criteria for the study will be randomized to sham stimulation. Stimulation will be performed 3 times per week, for 5 weeks (15 treatments). In this group, stimulation will be performed with the following features: Intensity of stimulation: 120% of the resting Motor Threshold (rMT), Frequency: 18 Hz (50% of patients) and 1 Hz (50% of patients), Duration of the train: 2 sec or 10 min, Inter-train interval: 20 sec or 1 min, Trains number: 80 or 4, Total pulses: 2880 or 2400, Total treatment duration: 29.3 or 43 min, Cue (sight of food preferred by patient): present. | Device: Sham<br>* Sham stimulation will be performed by an H-sham-coil. The H-sham-coil is designed to mimic the auditory artifacts and the scalp sensation evoked by the real coil, without stimulating the brain itself. As in the other groups, in each patient the rMT will be determined before each repetitive dTMS session. The sham stimulation will be performed either at high frequency (50% of subjects) or at low-frequency (50% of subjects), according to the previously described methodologies. All obese people in this group will be submitted at the sight of food preferred (cue).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in food craving levels induced by repetitive dTMS from baseline at 5 weeks | Food craving will be evaluated by the Food Cravings Questionnaire-Trait (FCQ-T), a self-report multidimensional questionnaire composed of 39 items aimed to investigate food addiction and eating disorders. Total FCQ-T score will be used as a general measure of trait craving; individual FCQ-T scores related to the 9 measured craving dimensions could be useful in identifying and differentiating craving profiles between specific populations. Food craving will be also evaluated at follow-up visit 1 (1 month after the end of treatment), follow-up visit 2 (6 months after the end of treatment), and follow-up visit 3 (1 year after the end of treatment). | Baseline and end of treatment (5 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in body weight induced by repetitive dTMS from baseline at 5 weeks | To evaluate the effectiveness of repetitive dTMS on body weight, the variation rate in kilograms of body weight between baseline and after 5 weeks will be considered. Body weight will be also evaluated at the 3 follow-up visits. | Baseline and end of treatment (5 weeks) | 
| Changes in Fat Mass (FM) rate induced by repetitive dTMS from baseline at 5 weeks | Changes in body composition, specifically in FM percentage (%), will be evaluated by body densitometry at the end of treatment compared to baseline. FM rate will be also evaluated at the follow-up visit 2 | Baseline and end of treatment (5 weeks) | 
| Acute and chronic changes in insulin levels induced by repetitive dTMS from baseline at 5 weeks | To identify acute and chronic changes induced by repetitive dTMS on the neuro-endocrine pathway involved in the hunger/satiety balance, the following parameter will be considered: insulin (microU/mL). Insulin will be evaluated acutely (before and immediately after the first and the last rTMS sessions) and chronically (at baseline, at end of treatment and at the 3 follow-up visits). | Baseline and end of treatment (5 weeks) | 
| Acute and chronic changes in glucagon levels induced by repetitive dTMS from baseline at 5 weeks | To identify acute and chronic changes induced by repetitive dTMS on the neuro-endocrine pathway involved in the hunger/satiety balance, the following parameter will be considered: glucagon (pg/mL). Glucagon will be evaluated acutely (before and immediately after the first and the last rTMS sessions) and chronically (at baseline, at end of treatment and at the 3 follow-up visits). | Baseline and end of treatment (5 weeks) | 
| Acute and chronic changes in ghrelin levels induced by repetitive dTMS from baseline at 5 weeks | To identify acute and chronic changes induced by repetitive dTMS on the neuro-endocrine pathway involved in the hunger/satiety balance, the following parameter will be considered: ghrelin (pg/mL). Ghrelin will be evaluated acutely (before and immediately after the first and the last rTMS sessions) and chronically (at baseline, at end of treatment and at the 3 follow-up visits). | Baseline and end of treatment (5 weeks) | 
| Acute and chronic changes in leptin levels induced by repetitive dTMS from baseline at 5 weeks | To identify acute and chronic changes induced by repetitive dTMS on the neuro-endocrine pathway involved in the hunger/satiety balance, the following parameter will be considered: leptin (ng/mL). Leptin will be evaluated acutely (before and immediately after the first and the last rTMS sessions) and chronically (at baseline, at end of treatment and at the 3 follow-up visits). | Baseline and end of treatment (5 weeks) | 
| Acute and chronic changes in Growth Hormone (GH) levels induced by repetitive dTMS from baseline at 5 weeks | To identify acute and chronic changes induced by repetitive dTMS on the neuro-endocrine pathway involved in the hunger/satiety balance, the following parameter will be considered: GH (ng/mL). GH will be evaluated acutely (before and immediately after the first and the last rTMS sessions) and chronically (at baseline, at end of treatment and at the 3 follow-up visits). | Baseline and end of treatment (5 weeks) | 
| Acute and chronic changes in Adreno-Cortico-Tropic Hormone (ACTH) levels induced by repetitive dTMS from baseline at 5 weeks | To identify acute and chronic changes induced by repetitive dTMS on the neuro-endocrine pathway involved in the hunger/satiety balance, the following parameter will be considered: ACTH (pg/mL). ACTH will be evaluated acutely (before and immediately after the first and the last rTMS sessions) and chronically (at baseline, at end of treatment and at the 3 follow-up visits). | Baseline and end of treatment (5 weeks) | 
| Acute and chronic changes in Thyroid-Stimulating Hormone (TSH) levels induced by repetitive dTMS from baseline at 5 weeks | To identify acute and chronic changes induced by repetitive dTMS on the neuro-endocrine pathway involved in the hunger/satiety balance, the following parameter will be considered: TSH (microUI/mL). TSH will be evaluated acutely (before and immediately after the first and the last rTMS sessions) and chronically (at baseline, at end of treatment and at the 3 follow-up visits). | Baseline and end of treatment (5 weeks) | 
| Acute and chronic changes in Prolactin levels induced by repetitive dTMS from baseline at 5 weeks | To identify acute and chronic changes induced by repetitive dTMS on the neuro-endocrine pathway involved in the hunger/satiety balance, the following parameter will be considered: Prolactin (ng/mL). Prolactin will be evaluated acutely (before and immediately after the first and the last rTMS sessions) and chronically (at baseline, at end of treatment and at the 3 follow-up visits). | Baseline and end of treatment (5 weeks) | 
| Acute and chronic changes in Cortisol levels induced by repetitive dTMS from baseline at 5 weeks | To identify acute and chronic changes induced by repetitive dTMS on the neuro-endocrine pathway involved in the hunger/satiety balance, the following parameter will be considered: Cortisol (microg/dL). Cortisol will be evaluated acutely (before and immediately after the first and the last rTMS sessions) and chronically (at baseline, at end of treatment and at the 3 follow-up visits). | Baseline and end of treatment (5 weeks) | 
| Acute and chronic changes in Neuropeptide Y levels induced by repetitive dTMS from baseline at 5 weeks | To identify acute and chronic changes induced by repetitive dTMS on the neuro-endocrine pathway involved in the hunger/satiety balance, the following parameter will be considered: Neuropeptide Y (pg/mL). Neuropeptide Y will be evaluated acutely (before and immediately after the first and the last rTMS sessions) and chronically (at baseline, at end of treatment and at the 3 follow-up visits). | Baseline and end of treatment (5 weeks) | 
| Changes in Beta-endorphin levels induced by repetitive dTMS from baseline at 5 weeks | Changes in neurophysiological mechanisms involved in satiety will be evaluated by dosing the main neurotransmitters involved in the reward system, like Beta-endorphins (ng/mL). Beta-endorphins will be evaluated acutely (before and immediately after the first and the last rTMS sessions) and chronically (at baseline, end of treatment and follow-up visits). | Baseline and end of treatment (5 weeks) | 
| Changes in Epinephrine levels induced by repetitive dTMS from baseline at 5 weeks | Changes in neurophysiological mechanisms involved in satiety will be evaluated by dosing the main neurotransmitters involved in the reward system, like Epinephrine (pg/mL). Epinephrine will be evaluated acutely (before and immediately after the first and the last rTMS sessions) and chronically (at baseline, end of treatment and follow-up visits). | Baseline and end of treatment (5 weeks) | 
| Changes in Norepinephrine levels induced by repetitive dTMS from baseline at 5 weeks | Changes in neurophysiological mechanisms involved in satiety will be evaluated by dosing the main neurotransmitters involved in the reward system, like Norepinephrine (pg/mL). Norepinephrine will be evaluated acutely (before and immediately after the first and the last rTMS sessions) and chronically (at baseline, end of treatment and follow-up visits). | Baseline and end of treatment (5 weeks) | 
| Changes in Glucose levels induced by repetitive dTMS from baseline at 5 weeks | Changes in glucose metabolism will be evaluated by glucose (mg/dL). Glucose will be measured acutely (before and immediately after the first and the last rTMS sessions) and chronically (at baseline, end of treatment and follow-up visits). | Baseline and end of treatment (5 weeks) | 
| Changes in Glycated Hemoglobin levels induced by repetitive dTMS from baseline at 5 weeks | Changes in glucose metabolism will be evaluated by Glycated Hemoglobin (mmol/mol). Glycated Hemoglobin will be measured chronically (at baseline, end of treatment and follow-up visits). | Baseline and end of treatment (5 weeks) | 
| Changes in Cholesterol levels induced by repetitive dTMS from baseline at 5 weeks | Changes in lipid metabolism will be evaluated by Cholesterol (mg/dL). Cholesterol will be measured acutely (before and immediately after the first and the last rTMS sessions) and chronically (at baseline, end of treatment and follow-up visits). | Baseline and end of treatment (5 weeks) | 
| Changes in Triglyceride levels induced by repetitive dTMS from baseline at 5 weeks | Changes in lipid metabolism will be evaluated by Triglycerides (mg/dL). Triglycerides will be measured acutely (before and immediately after the first and the last rTMS sessions) and chronically (at baseline, end of treatment and follow-up visits). | Baseline and end of treatment (5 weeks) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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fMRI, Obesity, Transcranial Magnetic Stimulation, Food Craving, Appetite/Satiety Hormones, Intestinal microbiota, Physical activity