Accelerated rTMS in Gambling Disorder: a Multicentric, Randomized, Sham-controlled Trial

Study Overview
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Brief Summary
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Background: Gambling disorder (GD), is a behavioral addiction based on keeping play despite medical, economic and social consequences. GD is characterized by progressive and persistent brain circuits alterations (reward, stress, memory, impulse control and cognitive functions), so a possible treatment could be based on neuromodulation of specific brain areas. Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation, which provides magnetic stimuli on certain brain areas parts with short and long-term effects. rTMS has the FDA approval for some neurological (headache) and psychiatric (treatment-resistant depression, obsessive-compulsive disorder) disease. Nowadays several evidence in scientific literature lead to a promise use of rTMS also in addiction field with a possible indication also for GD. Objectives: the main outcome is to assess symptoms related to GD (craving, play frequencies, money lost) before and after rTMS stimulation on left dorsolateral prefrontal cortex (DLPFC). Eligibility: Healthy, right-handed adults ages 18-65 with a diagnosis of GD. Design: This is a randomized, sham-controlled study. The study includes two phases:1) a rTMS continued treatment phase and 2) a follow-up without rTMS stimulation (30 days). In order to be enrolled, participants will be screened with: Questionnaires Medical history Physical exam f-MRI After being enrolled, baseline behavioral and imaging data will be collected. In particular, participants will submit: Questionnaires Functional MRI Cognitive tasks During the continued rTMS phase, participants with gambling disorder will be randomized to receive real or sham rTMS. RTMS will be delivered during 5 outpatient treatment days, (3 times/die). After the last stimulation and at the end of the 30-days of follow-up period, subjects will undergo the neurocognitive and psychometric evaluation. Twenty randomized patients of whole enrolled group will undergo fMRI at baseline and at the end of arTMS treatment phase. Treatment includes: rTMS: A weak electrical current passes through a coil placed on the head. During each stimulation day, participants will receive three rTMS sessions (13 min), with a 50 min of interval. fMRI: Participants lie on a table that slides into a cylinder that takes pictures of the brain. They respond to images while in the scanner. Repeat of screening tests and questionnaires

Detailed Description
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Repetitive Transcranial Magnetic Stimulation (rTMS) is a neurostimulation technique that consists in the application of magnetic pulses in order to modulate local brain activity, opened up the possibility of interacting with dysfunctional brain circuits, selectively targeting gambling-related cognitive dysfunction. The main outcome of the present study is to evaluate, in a population of GD patients, the effects of accelerated rTMS (arTMS) applied on Left Dorsolateral Prefrontal Cortex (LDLPFC) in terms of variations in gambling-related symptoms. In order to investigate the possible effects of arTMS on brain connectivity, a subsample of patients will undergo a functional neuroimaging study based on fMRI. The study includes 3 psychiatric assessments with psychometric testing: V1 (enrollment), V2 (day 5), V3 (week 4, follow-up). At Visit 1 (enrollment) the researcher will fully inform the patient about the study, obtaining the patient's informed consent to participate in the study, and will determine the patient's eligibility. Patients will also undergo a battery of cognitive tasks and psychometric evaluation. The same neurocognitive and psychiatric assessment will be repeated during Visit 2 (day 5) and Visit 3 (4 Weeks). The analysis of the neuroimaging data will allow to evaluate the effect of the active arTMS on brain connectivity (reward system, attention and executive control networks) investigate the association between these evidence and clinical variables.

Official Title
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Accelerated rTMS in Gambling Disorder: a Multicentric, Randomized, Sham-controlled Trial

Conditions
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Gambling, Gambling Disorder, Gambling, Pathological, Gambling Problem

Intervention / Treatment
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* Device: Accelerated repetitive Transcranial Magnetic Stimulation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Current diagnosis of Gambling Disorder, based on the Diagnostic and Statistical Manual of Mental Disorder - Fifth Edition (DSM-5); Exclusion Criteria: Current or pre-existing DSM-5 diagnosis of schizophrenia, bipolar disorder, or other psychotic disorder; Use in the past 4 weeks of any medication with known pro-convulsant action, including antipsychotic medications, tricyclic antidepressants, and antihistamines drugs; Medical history with significant neurological disorder, including organic brain disease, epilepsy, stroke, brain lesions and multiple sclerosis, previous neurosurgery, or personal history of head trauma that resulted in loss of consciousness for > 5 minutes and retrograde amnesia for > 30 minutes; Any personal or family history (1st degree relatives) of seizures other than febrile childhood seizures; Any psychiatric, medical or social condition whether or not listed above, due to which, according to the judgment of the PI and after any consults if indicated, participation in the study is not in the best interest of the patient; For female patients: Pregnancy/breastfeeding.

Ages Eligible for Study
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Minimum Age: 18 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
Interventional Model Description: double blind, randomized, sham-controlled with a 1:1 allocation into 2 parallel arms
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active arTMS (15 Hz)<br>The treatment involves 15 Repetitive Transcranial Magnetic Stimlation sessions (3/daily for 5 consecutive days, each session lasts 13 min with an interval of 50 min). Coil is placed on the left dorsolateral prefrontal cortex (LDLPFC).The stimulation has a frequency of 15 Hz and a intensity of 120% of the individual resting motor threshold. | Device: Accelerated repetitive Transcranial Magnetic Stimulation<br>* arTMS is a non-invasive brain stimulation technique. It will be used a MagPro R30 with a Cool-B80 figure-of-eight coil (MagVenture, Falun, Denmark).<br>* Other names: arTMS;|
| Sham Comparator: Sham arTMS<br>Sham group receives the same Repetitive Transcranial Magnetic Stimlation sessions of active compactors. However the interventions in the place group are with a superficial stimulation of scalp muscles only, in order to induce a sensation close to the one experienced with the real rTMS stimulation. | Device: Accelerated repetitive Transcranial Magnetic Stimulation<br>* arTMS is a non-invasive brain stimulation technique. It will be used a MagPro R30 with a Cool-B80 figure-of-eight coil (MagVenture, Falun, Denmark).<br>* Other names: arTMS;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in gambling behavior assessed by Yale Brown Obsessive Compulsive Scale adapted for Pathological Gambling (PG-YBOCS) | To assess the severity of gambling-related symptoms: Yale Brown Obsessive Compulsive Scale adapted for Pathological Gambling (PG-YBOCS), 10-item clinician-administered questionnaire that assess gambling symptoms over a recent time interval | Baseline, after rTMS treatment (5 day), 4 weeks | 
| Change in gambling behavior assessed by Gambling Symptom Assessment Scale (G-SAS) | a self-rated 5-point Likert scale with total score ranges from 0 to 48 | Baseline, after rTMS treatment (5 day), 4 weeks | 
| Change in gambling behavior assessed by TimeLine Follow Back (TLFB) - Gambling Version | in a multidimension retrospective interview focused on the quantitative assessment of gambling behavior | Baseline, after rTMS treatment (5 day), 4 weeks | 
| Change in gambling behavior assessed by Visual Analogue Scale | an instrument applied to assess continuum variables, using a horizontal line on which the patient shell point his current state from left vertex (no gambling craving) to right vertex (maximum gambling craving). | Baseline, after rTMS treatment (5 day), 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in attention / hyperactivity symptoms assessed by Adult ADHD Self-Report Scale (ASRS) | 5-Likert questionnaire to assess the presence of disturbing symptoms attention / hyperactivity | Baseline, after rTMS treatment (5 day), 4 weeks | 
| Change in emotional awareness assessed by Toronto Alexithymia Scale (TAS-20) | a self-report 5 point Likert scale with 20 items to assess emotional awareness. The total score goes from 20 to 100: non-alexithymia when the score is less than 51, borderline from 51 to 60 and alexithymia if the score is over 60 | Baseline, after rTMS treatment (5 day), 4 weeks | 
| Change in mood state assessed by Profile of Mood States (POMS) | a self-report, 5-point Likert scale to measure the current mood state through six dimensions of affect, including tension-anxiety, depression-dejection, anger-hostility, vigor-activity, fatigue-inertia, and confusion-bewilderment | Baseline, after rTMS treatment (5 day), 4 weeks | 
| Change in search for sensations assessed by Sensation Seeking Scale V (SSS-V) | a scale created with the purpose of understanding traits as neuroticism, antisocial behavior and psychopathy. There are four different subscales: Thrill and Adventure Seeking, Disinhibition,Experience Seeking, Boredom Susceptibility. Each subscale contains 10 items, making a total of 40 items | Baseline, after rTMS treatment (5 day), 4 weeks | 
| Change in hedonic tone assessed by Snaith-Hamilton Pleasure Scale (SHAPS) | a 14-item 4-point scale with a total score from 0 to 42 | Baseline, after rTMS treatment (5 day), 4 weeks | 
| Change in hedonic tone assessed by Temporal Experience of Pleasure Scale (TEPS) | a 18-item 6-point scale with a range from 20 to 108 | Baseline, after rTMS treatment (5 day), 4 weeks | 
| Change in quality of life assessed by Quality of Life Enjoyment and Satisfaction Questionnaire - Short Form (Q-LES-Q-SF) | to measure the social bonds of the subject with family members, friends, etc; this questionnaire is designed to help assess the degree of enjoyment and satisfaction experienced during the past week. There are 8 subscales : Phisical health, feelings, work, household duties, school/cpurse work, leisure time activities, social relations, general activities. | Baseline, after rTMS treatment (5 day), 4 weeks | 
| Change in suicidal behaviours assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) | The scale identifies specific behaviors which may be indicative of an individual's intent to complete suicide. An individual exhibiting even a single behavior identified by the scale was 8 to 10 times more likely to complete suicide | Baseline, after rTMS treatment (5 day), 4 weeks | 
| Change in psychopathological symptoms assessed by SCL-90 | measuring both internalizing symptoms (depression, somatization, anxiety) and externalizing ones (aggression, hostility, impulsiveness) of psychiatric patients, general medicine and non-clinical subjects | Baseline, after rTMS treatment (5 day), 4 weeks | 
| Change in food craving assessed by Food craving questionnaire (FCI) | a self-report 5-point Likert scale assess to evaluate food craving. The questionnaire consists of 28 items collected in 4 subscale: high fat foods, sweets, carbohydrates, fast foods | Baseline, after rTMS treatment (5 day), 4 weeks | 
| Change in sleep quality assessed by Insomnia severity index (ISI) | a self-report 5-point Likert questionnaire to estimate sleep quality in the last month. The total score range is from 0 to 28, in particular: absence of insomnia (0-7); sub-threshold insomnia (8-14); moderate insomnia (15-21); and severe insomnia (22-28) | Baseline, after rTMS treatment (5 day), 4 weeks | 
| Change in nicotine craving assessed by Short Tobacco Craving Questionnaire (sTCQ) | a Likert based scale (1-7 score) to evaluate nicotine craving. The questionnaire consisted in 4 domines (emotionally, expectancy, compulsivity, purposufullness), each with 3 items | Baseline, after rTMS treatment (5 day), 4 weeks | 
| Change in anxiety level assessed by Hamilton Anxiety Scale (HAM-A) | a 14-item 5-point scale with a total range score from 0 (min ) to 56 (max), that assesses anxiety symptoms exploring different domains anxious mood, tension or fears | Baseline, after rTMS treatment (5 day), 4 weeks | 
| Change in depressive symptoms assessed by Hamilton Depression Scale (HAM-D) | a interview with 20 items and total score is considered normal with range 0-7 | Baseline, after rTMS treatment (5 day), 4 weeks | 
| Change in manic symptoms assessed by Young Mania Rating Scale (YMRS) | a 11-item interview with total range score form 0 to 60 | Baseline, after rTMS treatment (5 day), 4 weeks | 
| Change in positive and negative symptoms assessed by Positive Affect and Negative Affect Scales (PANAS) | to measure any possible Collateral effect. PANAS is a 20-items 5-poin Likert questionnaire consisted in 2 subscale: Positive Affect Score and Negative Affect Score, with total range from 10 to 50 for each domains | Baseline, after rTMS treatment (5 day), 4 weeks | 
| Change in impulsivness assessed by Barratt Impulsiveness Scale (BIS-11) | a 11-items self-report questionnaire to evaluate temperamental impulsive traits. BIS-11 consists in 3 subscale: Attentional Impulsivity, Motor Impulsivity and Nonplanning Impulsivity | Baseline, after rTMS treatment (5 day), 4 weeks | 
| Change in cognitive performance by Iowa gambling task (IGT) | a psychological task thought to simulate real-life decision making. Participants are presented with four virtual decks of cards on a computer screen. They are told that each deck holds cards that will either reward or penalize them, using game money. The goal of the game is to win as much money as possible. The decks differ from each other in the balance of reward versus penalty cards | Baseline, after rTMS treatment (5 day), 4 weeks | 
| Change in cognitive performance by Go / No-Go Task | used to measure a participants capacity for sustained attention and response control. For example, a go/no-go test that requires a participant to perform an action given certain stimuli (e.g., press a button - Go) and inhibit that action under a different set of stimuli (e.g., not press that same button - No-Go). | Baseline, after rTMS treatment (5 day), 4 weeks | 
| Change in cognitive performance by Stroop color-word task | a neuropsychological test extensively used to assess the ability to inhibit cognitive interference that occurs when the processing of a specific stimulus feature impedes the simultaneous processing of a second stimulus attribute, well-known as the Stroop Effect | Baseline, after rTMS treatment (5 day), 4 weeks | 
| Change in cognitive performance by Wisconsin card-sorting task | a neuropsychological test of set-shifting, i.e. the ability to display flexibility in the face of changing schedules of reinforcement. A number of stimulus cards are presented to the participant. The original WCST used paper cards and was carried out with the experimenter on one side of the desk facing the participant on the other | Baseline, after rTMS treatment (5 day), 4 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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arTMS, Transcranial Magnetic Stimulation, TMS, Gambling Disorder