Exploring the Potential of High-frequency Repetitive Transcranial Magnetic Stimulation (rTMS) to Treat Gambling Disorder (GD)
Phase: NA
Conditions: Gambling Disorder
Sponsor: ITAB - Institute for Advanced Biomedical Technologies

Repetitive Transcranial Magnetic Stimulation in Gambling Disorder, part 1: open study.
Abbreviated title: Transcranial Magnetic Stimulation for Gambling Disorder
Protocol Number: 1561
Date of Approval: October 19, 2017
Principal Investigator
Name, Degree
Branch/Institute
Phone
E-mail
Massimo di 
Giannantonio, 
MD
Dept. of 
Neuroscience, 
Imaging and Clinical 
Sciences (ITAB) – 
University of Chieti
+39 0871358928
digiannantonio@unich.it
Co- Principal Investigator 
Name, Degree
Branch/Institute
Phone
E-mail
Giovanni 
Martinotti, M.D., 
Ph.D.
Dept. of 
Neuroscience, 
Imaging and Clinical 
Sciences (ITAB) – 
University of Chieti
Villa Maria Pia Clinic 
- Rome
+39 08713556914
Giovanni.martinotti@gmail.com
Associate Investigators 
Name, Degree
Branch/Institute
Phone
E-mail
Chiara 
Montemitro, 
M.D.
MNB/NINDS
+39 3281264713
Chiara.montemitro@gmail.com
Mauro 
Pettorruso, M.D.
MNB/NINDS
+39 3391979487
mauro.pettorruso@hotmail.it
Lamberto 
Manzoli, Ph.D.
Office of 
Biostatistics/
University of 
Ferrara
+39 3474727282
Lamberto.manz@yahoo.com
Referral Contact 
Name, Degree
Branch/Institute
Phone
E-mail
Mauro Pettorruso, 
M.D.
MNB/NINDS
+39 3391979487
mauro.pettorruso@hotmail.it
Accountable Investigator
Name, Degree
Branch/Institute
Phone
E-mail
1

Giovanni 
Martinotti, M.D., 
Ph.D.
Dept. of 
Neuroscience, 
Imaging and Clinical 
Sciences (ITAB) – 
University of Chieti
Villa Maria Pia Clinic 
- Rome
+39 08713556914
Giovanni.martinotti@gmail.com
2

A. Précis
Background: Gambling Disorder (GD) is a complex addictive disorder involving fronto-
striatal connectivity and prefrontal top-down control modulation of reward-related brain 
areas. Repetitive transcranial magnetic stimulation (rTMS) seems to reduce cravings and 
improve cognitive function in substance dependent individuals. Moreover, rTMS has been 
shown to modulate dopaminergic and glutamatergic transmission, both involved in GD 
pathophysiology. However, the efficacy of rTMS in treating GD has not been evaluated and 
also, we lack a full characterization of rTMS effects on other important aspects, including 
effects on mood, cognition and changes in brain function.
Objectives: The primary goal of the current study is to investigate the effects of repetitive 
transcranial magnetic stimulation (rTMS) targeting the left DLPFC on gambling craving. The 
co-primary goal is to investigate rTMS effect on gambling behavior.  Our secondary goals are 
to evaluate rTMS effects on: (1) mood; (2) cognitive functions. 
Study population: Treatment seeking subjects affected by Gambling Disorder, aged 18-65 
years
Design: After eligibility screening and informed consent, participants will undergo a baseline 
phase during which they will be randomized to receive high-frequency (15Hz) rTMS (active 
rTMS) stimulation of the left DLPFC. Subsequently, the continued treatment phase will take 
place, during which rTMS sessions will be conducted twice per day, five times per week for 2 
weeks, for a total of 20 sessions. During this phase, participants will also undergo self-help 
groups twice a week. After this phase, participants will start a 24-week outpatient phase. (2) 
During the first 12 weeks (rTMS follow-up) participants will undergo real stimulation (two 
consecutive sessions weekly), and behavioral assessments will be performed.
During the following 12 weeks (no rTMS follow-up), participants will not receive TMS but 
behavioral data will be collected to observe long-term effects of rTMS. Visits will take place 
every two weeks, during this phase. During the follow-up period, patients will continue to 
participate in self-help groups.
Outcomes measures: Our primary outcomes will be: (1) change in craving score as measured 
by the Visual Analogue  Scale for Craving  (VAS-craving) from pre- to post treatment 
[baseline and after rTMS treatment: 2 weeks, 3 months, 6 months]; (2) changes in gambling 
behavior as measured by TLFB self-reports, Pathological Gambling Adaptation of the Yale-
Brown Obsessive-Compulsive Scale (PG-YBOCS), Gambling Symptom Assessment Scale 
3

(G-SAS) [baseline and after rTMS treatment: 2 weeks, 3 months, 6 months]. Our secondary 
outcomes  are: Changes in the scores on the the Montgomery-Asberg Depression Scale 
(MADRS) from pre- to post treatment [baseline and after rTMS treatment: 2 weeks, 3 
months, 6 months]; (2) changes in the scores on the Hamilton Anxiety Rating Scale (HAM-
A); (3) changes in the scores of the Iowa Gambling Task from pre- to post treatment [baseline 
and after rTMS treatment: 2 weeks, 3 months, 6 months]; (4) changes in the scores of the 
anhedonic symptoms assessed by Snaith Hamilton Pleasure Scale (SHAPS) and Temporal 
experience of Pleasure Scale (TEPS) from pre- to post treatment [baseline and after rTMS 
treatment:  2 weeks, 3 months, 6 months]; (5) changes in the scores of the anhedonic 
symptoms assessed by changes in Profile of Mood States (POMS) from pre- to post treatment 
[baseline and after rTMS treatment: 2 weeks, 3 months, 6 months].
4

B. Background
Gambling disorders
The neural background of Gambling Disorder has been recently shown by brain imaging 
technologies:  current evidences  corroborate  a crucial  role of prefrontal  network in the 
complex construct of cognitive control (Moccia, Pettorruso et al., 2017). GD patients showed 
increased functional connectivity between regions of the PFC and mesolimbic reward system, 
as well as reduced connectivity in the area of the PFC, suggesting an imbalance between 
prefrontal areas and the mesolimbic reward system (Bechara, 2005; Heatherton and Wagner, 
2010). This finding in GD is very similar to what has been reported in SUDs, suggesting a 
common pathophysiology for addictive disorders (Meng et al., 2014). Growing evidence 
suggest the potential importance of the fronto-striatal cortical pathway in the clinical control 
of GD severity, emphasizing a deficiency in the top-down inhibitory control of reward-
related brain areas (Koehler et al., 2013). These developments in GD comprehension have 
been accompanied by advances in neuromodulation interventions, both invasive as deep brain 
stimulation,  and  non-invasive  such  as  repetitive  transcranial  magnetic  stimulation  and 
transcranial direct current stimulation. These interventions appear particularly promising as 
they may not only allow us to probe affected brain circuits in addictive disorders, but also 
seem to have unique therapeutic applications to directly target and remodel impaired circuits.
Neuromodulation: Transcranial Magnetic Stimulation
rTMS, a non-invasive brain stimulation technique, has been used in experimental approaches 
to a variety of neuropsychiatric disorders (George et al., 2002). rTMS can alter cortical 
excitability, and hence induce changes in neuronal circuits (Fitzgerald et al. 2009, Cho & 
Strafella 2009). TMS generates electrical activity in localized brain regions following through 
the application of magnetic pulses produced by passing an electrical current through an 
electromagnetic coil. The direct effect on underlying brain tissue can be sufficiently focused 
to allow a mapping of the motor cortex (Wilson et al., 1993). MRI or Positron Emission 
Tomography (PET) studies of the cortical region stimulated by TMS have shown it to be 
reasonably delimited, and approximately the same size as that involved with voluntary 
movements of single fingers (Bohning et al., 2000a; Bohning et al., 2000b; Takano et al., 
2004).  The magnetic stimulation can be delivered as a single pulse or as a train of pulses. 
Initially used on the motor cortex, a single TMS pulse caused activation of a motor response. 
When applied as a train, supra-threshold rTMS at high frequencies (≥5Hz) caused a long-
5

lasting facilitation of motor cortex excitability, whereas at low frequency (1 Hz) it caused a 
long-lasting inhibition (Siebner & Rothwell, 2003).  In general, the longer the train of stimuli, 
the greater the duration of either facilitation or inhibition.  With a constant frequency, the 
effects last approximately 50-60% of the duration of the stimulus train. In a typical “figure 
eight” coil, the intensity of the magnetic field induced by current running through the coil is 
maximal under the cross point of the “eight,” near the cortical surface of the brain, therefore 
allowing for a focal stimulation of cortical areas. In addiction research, rTMS and other brain 
stimulation techniques have been mainly used as investigative tools to index altered cortical 
excitability induced by chronic exposure to drugs of abuse. Most of these studies were 
conducted to assess changes in excitability of the motor cortex (Boutros et al., 2001, 2005; 
Lang et al., 2008; Sundaresan et al., 2007; Ziemann et al., 1995). Recently, however, repeated 
brain stimulation using TMS has also been evaluated for its potential efficacy in reducing 
drug craving and associated addictive behaviors. In these studies, stimulation was typically 
applied to the DLPFC, and its ability to affect drug consumption and craving was measured 
(Amiaz et al., 2009; Camprodon et al., 2007; Eichhammer et al., 2003; Johann et al., 2003; 
Politi et al., 2008). In particular, three studies evaluated the effects of high-frequency rTMS 
in individuals  with cocaine addiction. Camprodon and colleagues  (2007) compared the 
effects  of a single session of rTMS  (10 Hz) targeting  either  right  or left  DLPFC on 
spontaneous craving in six subjects. Right but not left rTMS reduced craving although these 
findings were limited by the small sample and absence of a sham control.  Findings from a 
subsequent study show that targeting the left DLPFC with high-frequency rTMS may also 
have an anti-craving effect (Politi et al., 2008). This was an open-label study in which 36 
cocaine-dependent  individuals  received  10 daily  sessions  of  active  rTMS  and  reported 
decreased spontaneous cocaine craving.  More recently, Terraneo and colleagues (Terraneo et 
al. 2015) also conducted another open-label pilot study with 32 cocaine addicted patients 
randomly assigned to receive 8 sessions of high-frequency rTMS of the left or standard 
pharmacological  treatment.  rTMS was associated  with decreased craving and increased 
abstinence rates, as assessed by the number of cocaine-free urine drug tests, compared to the 
control group.  Moreover, high-frequency rTMS of the medial prefrontal cortex (PFC) and 
continuous theta burst stimulation (cTBS) of the right dorsolateral PFC has been shown to 
reduce impulsive choice in healthy volunteers and to reduce gambling reinforcement in non-
comorbid men with PG (Zack et al, 2017). 
On the basis of these findings, the aim of this study is to test whether rTMS of the left 
DLPFC could be effective in treating GD. 
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C. Study Overview
This is an open-label study with a single arm: 15 Hz rTMS stimulation on the DLPFC. 
Participants will be 10 treatment-seeking patients, between the ages of 18-65, who meet 
diagnostic criteria for GD. Criteria for study enrollment are listed below. All participants will 
be informed about study procedures and will provide written informed consent prior to the 
experiment,  in  line  with  the  Helsinki  Declaration  developed  by  the  World  Medical 
Association.
Recruitment: We aimed to recruit patients from rural and urban areas, in order to take 
account of possible differences in substance consumption and addiction severity. Therefore, 
recruitment will take place in two different cities: Rome, a large metropolitan area, and 
Chieti, a small city in the center of Italy, where the majority of patients will be enrolled from 
rural surroundings. Participants enrollment will be performed by a multidisciplinary team 
(physicians,  psychologists),  who  have  been  trained  and  have  extensive  experience  in 
performing the assessments included in the current study.
Inclusion criteria
1. Age 18 – 65;
2. Current diagnosis of Gambling Disorder, based on the Diagnostic and Statistical Manual 
of Mental Disorder – Fifth Edition (DSM-5);
3. Drug-free.
Exclusion criteria
1. Current DSM-5 diagnosis of substance use disorders other than nicotine 
2. Current DSM-V diagnosis of moderate to severe alcohol use disorders 
3. Current DSM-5 diagnosis of schizophrenia, bipolar disorder, or other psychotic disorder; 
4. Use in the past 4 weeks of any medication with known proconvulsant action; or current 
regular use of any psychotropic medications (benzodiazepines, antipsychotic medications, 
tricyclic antidepressants, anti-epileptics, mood stabilizers);
7

5. Any history of any clinically significant neurological disorder, including organic brain 
disease, epilepsy, stroke, brain lesions, 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;
6. Any personal or family history (1st degree relatives) of seizures other than febrile 
childhood seizures;
7. Any psychiatric, medical or social condition whether or not listed above, due to which, in 
the judgment of the PI and after any consults if indicated, participation in the study is not 
in the best interest of the patient;
8. For female patients: Pregnancy/breastfeeding. 
Participants  enrollment  will  be  performed  by  a  multidisciplinary  team  (physicians, 
psychologists), who have been trained and have extensive experience in performing such 
assessments. Participants will be presented with information about the study prior to data 
collection and they will be informed of their right to withdraw their information at any time, 
and that by taking part they are providing consent for the research team to use their 
anonymised data for research (including publications and other forms of dissemination). 
Furthermore, they will provide written informed consent prior to the experiment, in line with 
the Helsinki Declaration developed by the World Medical Association. The research team 
will not include people if they are unable to give informed consent. The Health and Human 
Sciences Ethics Committee at the University of Chieti approved the research before it 
commences.
D. Procedures
rTMS
Repetitive TMS will be delivered using a MagPro R30 with the Cool-B80 figure-of-eight coil 
(MagVenture, Falun, Denmark).  Such coil allows for a focal stimulation of the DLPFC. 
Subjects will be seated in a recliner with their hands in a comfortable resting position, and the 
study investigator will insert earplugs, while the participant will wear a cap over the scalp. 
After skin preparation, surface electrodes will be taped over the region of the abductor 
pollicis brevis (APB) belly and associated tendon of the right hand. The coil will be placed 
over the hand-associated primary motor cortex of the right hemisphere with the handle 
8

directed posteriorly. While supra-threshold stimuli will be applied, the coil will be moved in 
steps of 1 cm to determine the optimal scalp position for producing motor evoked potentials 
(MEP) of maximal amplitude (lowest threshold) in the contralateral target hand muscle. This 
procedure will be performed in order to identify the resting motor threshold (RMT), which 
will be used to calculate the intensity of stimulation (100% of the RMT). Subsequently, the 
coil will be placed over the left dorsolateral prefrontal cortex using a TMS Navigator. The 
motor hotspot and the DLPFC location will be marked on the cap wore by the participant so 
to ensure accuracy and consistency across sessions.  Two consecutive rTMS sessions lasting 
13 minutes each will be performed, with a minimum of 60 minutes interval between sessions. 
Each rTMS session will be delivered at the intensity of 100% of individual resting motor 
threshold, for a total of 40 trains (60 stimuli per train, inter-train interval of 15 seconds, for a 
total of 2400 stimuli). At the beginning of each session, participants will be exposed to 
gambling-related cues for approx. 2 minutes. While viewing pictures (approx. 60 images), 
participants will be instructed to try to inhibit any craving elicited by the cues in an attempt to 
elicit  activation  in  networks  specifically  related  to  controlling  responses  and  gambling 
behavior in general. At the end of each stimulation session, participants will rate their craving 
using a Visual Analogue Scale (VAS). 
Study days during which participants will receive stimulation will be planned as follow:
1. Arrival
2. Tox drug screen
3. Preparation (earplugs, cap)
4. RMT*
5. TMS and gambling-cues exposure
6. HR/PB monitoring
7. VAS craving 
8. Side effects questionnaire and PANAS
9. Interval ≥ 60 minuti
10. Steps 6,7 and 8 will be repeated
Participants will receive 20 sessions of rTMS during the continued rTMS treatment phase (2 
sessions daily, 5 days/week), and subsequently will undergo 24 sessions during the follow-up 
(FU) phase (two consecutive sessions per day for 12 weeks), for a total of 44 sessions over 
the course of the study. 
During each stimulation session and immediately after, hearth rate and blood pressure will be 
monitored. Also, at the end of the session, the ‘Side Effect” questionnaire and the PANAS 
scale will be administered to evaluate potential side effects. 
9

Side effects: The use of rTMS is considered safe when conducted within existing safety 
guidelines (Rossi et al. 2009). On the basis of these guidelines, it has been developed a 
screening tool, named the  TMS safety screening, which will be administered to all study 
participants to determine their eligibility. Several side effects have been reported following 
TMS. The most important risk of rTMS is the possibility of inducing a seizure. The 1996 and 
2008 International Consensus Safety Guidelines describe the maximum safe duration of an 
rTMS train based on intensity and frequency of the stimulation. Since the issuance of these 
guidelines, the incidence of TMS-induced seizures worldwide is very low, estimated as “rare” 
with low-frequency (< 1 Hz) rTMS and < 1% with high-frequency (> 1 Hz) rTMS.  There 
have been no reports of any subject developing epilepsy or repeated spontaneous seizures 
after rTMS. All rTMS-induced seizures to date have been transient and self-limiting, without 
long-term sequelae.  
Concurrent medication has been implicated as a risk factor in some of the seizures reported 
with rTMS. Some have suggested that certain medications, e.g. tricyclic antidepressants and 
neuroleptics,  should  be  contraindicated  in  those  receiving  rTMS.   To  minimize  risk, 
psychotropic medications will be exclusionary criteria in the current study, and use of illicit 
drugs will be monitored.  Although data are lacking, a history of epilepsy, of seizures of other 
origin (other than febrile child fevers) could also be associated with an increase of TMS-
induced seizures, and will therefore also be exclusionary criteria. To manage the small risk 
nevertheless present, a physician will be available while TMS sessions are in progress and 
will be called in the event of any medical issue.   
Mild headache responding readily to non-opioid analgesics has been reported as onthe most 
common side-effect of rTMS reported in depression treatment trials. It may result from direct 
stimulation of superficial facial muscles or nerves, as rTMS may cause an uncomfortable 
facial twitch.  Headaches usually go away promptly with nonprescription medication, such as 
acetaminophen, which will be offered to subjects as needed. 
Hearing Impairment: Rapid excitation of the stimulation coil produces clicks that have 
resulted in transient increase in the auditory threshold of human subjects.  This should not 
occur if earplugs are used. If a subject report or if an investigator observes that a subject’s 
earplug has loosened or fallen out, investigators will immediately stop applying.
rTMS-Induced Manic Effects: Mania has been induced in a small number of healthy and 
depressed subjects by high-frequency rTMS to the left dorsolateral prefrontal cortex. 
In all the above cases, the psychiatric side-effects induced by rTMS were transient, resolving 
with the cessation of rTMS or rapidly responding to pharmacological treatment.  
10

Although  not  limited  to,  the  risk  for  psychiatric  complications  appears  to  be  existing 
predominantly in subjects with pre-existing psychiatric morbidity. An important means of 
minimizing  risk in the  current  proposed  study  is  therefore  to  exclude  this  population. 
Furthermore, mood symptoms will be monitored using a validated rating scale, and will 
provide an additional indication of hypomanic or manic symptoms (YMRS, PANAS, CPRS).
Questionnaires and Rating Scales
 
-
TMS Safety Screen:  A questionnaire that aids in determining appropriateness of 
administering TBS. Completion time: < 5 minutes.
-
Visual Analogue Scale for Craving (VAS-craving): VAS is a horizontal line, 100 mm 
in length, anchored by word descriptors at each end (0 = lower scores; 10 = higher 
scores). The patient  marks  on the  line  the  point that  they  feel  represents  their 
perception of their current state. Completion time: < 5 minutes.
-
Pathological Gambling Adaptation of the Yale-Brown Obsessive-Compulsive Scale 
(PG-YBOCS):  A  10-item  clinician-administered  questionnaire  that  measures  the 
severity of PG over the past one week. Completion time: < 5 minutes.
-
Gambling Symptom Assessment Scale (G-SAS): A 12-item self-rated scale designed 
to assess gambling symptom severity and change during treatment. Completion time: 
< 5 minutes.
As time permits during the screening visit and after consenting, baseline characterization 
measures will also be collected. Participants may be scheduled for an additional visit and the 
necessary additional time to complete these assessments prior to beginning the 10-day rTMS 
treatment  session. Following this, subjetcs  will have 8 follow-up visits  [at the end of 
continued rTMS treatment phase, at rTMS follow-up visit #2, #4, #8, #12, and once a month 
during no rTMS follow-up phase].
Characterization measures include:
-
Hamilton Anxiety Scale (HAM-A): A 21-item self-report inventory, which assesses 
the severity of anxiety. Completion time: ~ 5 minutes.
-
Montgomery-Asberg Depression Rating Scale (MADRS): A clinical assessment to 
identify symptoms of depression. This assessment is especially useful in identifying 
changes in depression symptoms over time. Completion time: < 10 minutes.
11

-
Positive and Negative Affect Scale (PANAS): A self-report scale to assess state-level 
affect. Completion time: < 5 Minutes.
-
Profile of Mood States (POMS): A questionnaire designed to measure present mood 
state by a list of adjectives on a 5-point Likert scale and measures six dimensions of 
affect, including tension-anxiety, depression-dejection, anger-hostility, vigor-activity, 
fatigue-inertia, and confusion-bewilderment. The measure has been shown to produce 
reliable and valid profiles of mood state. Completion time: ~ 5 minutes.
-
Snaith-Hamilton Pleasure Scale (SHAPS): A 14-item self-report scale designed to 
measure hedonic-tone/anhedonia. Completion time: ~ 5 minutes.
-
Temporal Experience of pleasure Scale (TEPS): A 20-item self-report scale designed 
to evaluate individual trait dispositions in anticipatory and consummatory pleasure 
experiences. Completion time: ~ 15 minutes.
-
Time-line follow back (TLFB). The TLFB will be used to assess substance use 
behavior. This assessment will be either self-administered or administered by one of 
the investigators. Participants will read the instructions and/or will be guided by the 
therapist  or  investigator  in  filling  out  the  calendar.  A  lifetime  TLFB  will  be 
administered at baseline and during each visit. 
Cognitive Function will be assessed at baseline, at the end of continued rTMS treatment 
phase, at the end of rTMS follow-up phase and at the end of the no rTMS follow-up phase. 
Cognitive Assessment include: 
-
Iowa Gambling Task: to assess decision-making process. Completion time: ~ 15 min.
E. Study Design
The study itself will consist of three phases.
(1)  an outpatient screening phase, during which patients will be screened to assess their 
eligibility  to  be  enrolled  in  the  study.  This  phase  will  include  informed  consent  and 
randomization, and will conclude with baseline data collection.
(2) a  continued rTMS treatment phase, during which subjects will receive 20 stimulation 
sessions (2 daily, 5 days/week). In addition to this, participants will also attend self-help 
groups twice per week, as part of standard-of-treatment for GD.
During this phase, treatment response will be assessed by evaluating the long-term effect of 
treatment on relapse rate, gambling severity and craving, mood and cognition.
12

(3) a follow-up phase of 24 weeks, which will be structured as following. During the first 12 
weeks (rTMS follow-up) subjects will be asked to return to the Outpatient Clinic for an 
outpatient  visit.  During  these  visits,  participants  will  undergo  real  stimulation  (two 
consecutive sessions per day), and will also attend self-help groups once per week. 
During the following 12 weeks (no rTMS follow-up), participants will not receive TMS but 
behavioral and other data will be collected to observe long-term effects of rTMS.
If subjects are unable or unwilling to attend these visits, they will be contacted by phone or 
email, and an attempt will be made to obtain measures in this manner. 
F. Objectives
Primary: The primary goal of the current study is to investigate the effects of repetitive 
transcranial magnetic stimulation (rTMS) targeting the left DLPFC on gambling craving. The 
co-primary goal is to investigate rTMS effect on gambling behavior.  
Secondary: Our secondary goals are to evaluate rTMS effects on: (1) mood; (2) cognitive 
functions. 
Outcomes measures: Our primary outcomes will be: (1) change in gambling craving score 
as measured by the Visual Analogue Scale for Craving (VAS-craving) from pre- to post 
treatment [baseline and after rTMS treatment: 2 weeks, 3 months, 6 months]; (2) changes in 
gambling behavior as measured by TLFB self-reports, Pathological Gambling Adaptation of 
the  Yale-Brown  Obsessive-Compulsive  Scale  (PG-YBOCS),  Gambling  Symptom 
Assessment Scale (G-SAS) [baseline  and after rTMS treatment:  2 weeks, 3 months, 6 
months]. Our secondary outcomes are: (1) Changes in the scores on the the Montgomery-
Asberg Depression Scale (MADRS) from pre- to post treatment [baseline and after rTMS 
treatment: 2 weeks, 3 months, 6 months]; (2) changes in the scores on the Hamilton Anxiety 
Rating Scale (HAM-A); (3) changes in the scores of the Iowa Gambling Task from pre- to 
post treatment [baseline and after rTMS treatment: 2 weeks, 3 months, 6 months]; (4) 
changes in the scores of the anhedonic symptoms assessed by Snaith Hamilton Pleasure Scale 
(SHAPS) and Temporal experience of Pleasure Scale (TEPS) from pre- to post treatment 
[baseline and after rTMS treatment: 2 weeks, 3 months, 6 months]; (5) changes in the scores 
of the anhedonic symptoms assessed by changes in Profile of Mood States (POMS) from pre- 
to post treatment [baseline and after rTMS treatment: 2 weeks, 3 months, 6 months].
13

1. Aims
Primary aim:
To determine the effects of rTMS on gambling craving and behavior in patients with GD. 

Changes in the Visual Analogue Scale for Craving (VAS-craving) from pre- to post 
treatment [baseline and after rTMS treatment: 2 weeks, 3 months, 6 months];

Changes in the Pathological Gambling Adaptation of the Yale-Brown Obsessive-
Compulsive Scale (PG-YBOCS) from pre- to post treatment [baseline and after rTMS 
treatment: 2 weeks, 3 months, 6 months].

Changes  in  Gambling  Disorder  Severity  as  assessed  by  Timeline  Follow  Back 
(TLFB) from pre- to post treatment [baseline and after rTMS treatment: 2 weeks, 3 
months, 6 months].

Change in Gambling Behavior as assessed by Gambling Symptom Assessment Scale 
(G-SAS) from pre- to post treatment [baseline and after rTMS treatment: 2 weeks, 3 
months, 6 months].
Secondary aims: 

Changes in the Iowa Gambling Task (IGT) Performance from pre- to post treatment 
[baseline and after rTMS treatment: 2 weeks, 3 months, 6 months]; 

Changes in the scores of the Montgomery-Asberg Depression Scale (MADRS) from 
pre- to post treatment [baseline and after rTMS treatment: 2 weeks, 3 months, 6 
months]; 

Changes in the scores on the Hamilton Anxiety Rating Scale (HAM-A) from pre- to 
post treatment [baseline and after rTMS treatment: 2 weeks, 3 months, 6 months];

Changes in the scores on the Snaith Hamilton Pleasure Scale (SHAPS) and on the 
Temporal experience of Pleasure Scale (TEPS) from pre- to post treatment [baseline 
and after rTMS treatment: 2 weeks, 3 months, 6 months];

Changes in the scores of the Profile of Mood States (POMS), from pre- to post 
treatment [baseline and after rTMS treatment: 2 weeks, 3 months, 6 months];
Statistical Analysis
Behavioral measures on each of the cognitive tasks as well as questionnaire data from 
each of the experimental conditions will be compared within the experimental group using 
14

mixed, repeated-measures ANOVA, and linear mixed models. When assessing the statistical 
results from the behavioral and questionnaire data, a standard α-level of 0.05 will be used. 
Alpha-levels for multiple comparison follow-up tests will be corrected using an appropriate 
method (e.g., Bonferroni, Tukey, Scheffe). 
15

G. Data Management and Safety measures
Safety: Participants  will  be  presented  with  information  about  the  study  prior  to  data 
collection and they will be informed of their right to withdraw their information at any time, 
and that by taking  part they are providing consent for the research team  to use their 
anonymised data for research (including publications and other forms of dissemination) 
(informed  consent  and  information  sheets  are  attached  as  annexes,  Italian  version). 
Furthermore, they will provide written informed consent prior to the experiment, in line with 
the Helsinki Declaration developed by the World Medical Association. The research team 
will not include people if they
are unable to give informed consent. The Health and Human Sciences Ethics Committee at 
the University of Chieti approved the research before it commences.
Randomization: We aimed to recruit a total of 10 patients for this open-label study. If data 
will suggest a potential role of rTMS in Gambling Disorder, we will proceed to a randomized 
placebo-controlled trial to verify our hypothesis. 
Data  collection  and  storage:  Collected  personal  data  will  be  identified  via  specific 
individual codes. Datasets will be anonymized by removing all direct identifiers, (e.g., name, 
address, telephone numbers), but also indirect identifiers and other information that could 
lead to "deductive disclosure" of participants' identities. The computer files will be password 
protected, and only accessed by agreed members of the team. Files will be shared to other 
involved institutions via secure server. Hard copies such as interview notes, questionnaires 
and psychometric scales will be kept securely locked in a cabinet that will only be accessed 
by agreed members of the research team. As a part of the informed consent, participants will 
be informed on what will happen to the data they will provide, and specifically: a) on how the 
data will be stored; b) on who will access the data; c) on how long the data will be kept for.
16

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