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Repetitive Transcranial Magnetic

Stimulation in Gambling Disorder

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validity of this study is the
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ClinicalTrials.gov Identifier: NCT03336879

Recruitment Status ! : Recruiting

First Posted ! : November 8, 2017
Last Update Posted ! : November 8,
2017

See Contacts and Locations

Sponsor:
ITAB - Institute for Advanced Biomedical
Technologies

Information provided by (Responsible

Party):
Giovanni Martinotti, ITAB - Institute for
Advanced Biomedical Technologies

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Study Go to
Description

Brief Summary:

Background: An imbalance between prefrontal

cortex (PFC) and the mesolimbic reward
system has been suggested to contribute to
GD. 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. The altered
interaction between prefrontal structures and
the mesolimbic reward system in GD shares
similarity with functional organization reported
in Substances Use Disorders (SUDs),
suggesting a more general pathophysiology for
addictive disorders

Objectives: To test if rTMS can reduce craving

and playing in Gambling Disorder, and also
affect several mood, behavioral and cognitive
alterations associated with prolonged
Gambling Disorder.

Eligibility: Healthy, right-handed adults ages

18-65 who do have Gambling Disorder.

Design: This is a non-randomized, open label

study. The study includes three phases: 1) a
rTMS continued treatment phase; 2) a rTMS
follow-up; and 3) a no rTMS follow-up.

Prior to participating, participants will be

screened with:

Questionnaires
Cognitive tests
Medical history
Physical exam

After being enrolled, baseline behavioral and

imaging data will be collected. In particular,
participants will undergo:

Questionnaires
Cognitive tests

During the continued rTMS phase, participants

with Gambling Disorder will receive real rTMS.
Repetitive TMS will be delivered during 10
outpatient treatment days, over 2 weeks (5
days/week). Following this phase, subjects will
have 12 follow-up visits (once/weekly), during
which they will receive rTMS, and behavioral
assessments will be performed. At the end of
the rTMS follow up period, participants will
further receive 3 follow up visits (once a
month), during which rTMS will not be
performed, but behavioral data will be
collected.

Treatment includes:

rTMS: A coil is placed on the head. Brief

electrical current passes through the coil.
At each visit, participants will receive two
rTMS sessions, with a 1hr interval between
sessions. At the beginning of each rTMS
session, they view gambling-related
images for few minutes.
Repeat of screening tests and
questionnaires

Condition
or Intervention/treatment
Phase !
disease !
!

Gambling Device: Repetitive Not Applica

Disorder Transcranial Magnetic
Stimulation

Detailed Description:

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. The purpose of this
study is to investigate the effects of repetitive
Transcranial Magnetic Stimulation (rTMS) at 15
Hz frequency on the left dorsolateral prefrontal
cortex in patients affected by GD and to
examine possible changes in mood, cognition,
and brain activity and functional connectivity
associated with this intervention. For this
purpose, the investigators will recruit GD
patients. After screening and informed
consent, participants will undergo active rTMS
for two consecutive weeks (twice a day) during
the continued treatment phase, and a
maintenance intervention (twice a week for 3
months), during the rTMS follow-up phase.
Following this phase, participants will be
followed for further 3 months, during which no
rTMS will be delivered but clinical data will be
collected.

Procedure: The project consists of: Screening

Visit (baseline), Phase 1 (continued treatment
phase), Phase 2 (3 months- rTMS follow-up),
Phase 3 (3 months follow-up without rTMS).
First, there will be a screening visit, where a
clinical interview will be conducted and
questionnaires and tests will be administered
to identify study participants who meet the
inclusion and exclusion criteria. Baseline
clinical and cognitive data will be acquired. In
Phase 1, participants will receive 2 sessions of
rTMS (active), twice per day for 10 consecutive
days, for a total of 20 rTMS sessions.
Following this, the investigators will evaluate
the acute effect of treatment on relapse rate,
gambling severity and craving, mood and
cognition. In Phase 2 of the study, all
participants will continue the treatment arm
with rTMS (15Hz) for three months.
Participants will receive 2 sessions of rTMS
(active) once per week; clinical and cognitive
data will be acquired once per month. The
investigators will evaluate the acute effect of
treatment on relapse rate, gambling severity
and craving, mood and cognition. In Phase 3
of the study, participants will not receive any
rTMS session. Clinical and cognitive data will
be acquired once per month for three months.
The investigators will evaluate the long-term
effect of treatment on relapse rate, gambling
severity and craving, mood and cognition.

Study Go to
Design

Study Type ! :
Interventional (Clinical Trial)

Estimated Enrollment ! :
10 participants

Allocation:
N/A

Intervention Model:
Single Group Assignment

Intervention Model Description:

non-randomized, open label study

Masking:
None (Open Label)

Primary Purpose:
Treatment

Official Title:
Exploring the Potential of High-frequency
Repetitive Transcranial Magnetic Stimulation
(rTMS) to Treat Gambling Disorder (GD)

Actual Study Start Date ! :

November 1, 2017

Estimated Primary Completion Date ! :

December 30, 2018

Estimated Study Completion Date ! :

December 30, 2020

Resource links provided by the

National Library of Medicine

MedlinePlus related topics:

Compulsive Gambling

U.S. FDA Resources

Arms and Go to
Interventions

Intervention/treatment
Arm !
!

Experimental: Device: Repetitive

Active rTMS (15 Transcranial Magnetic
Hz) Stimulation
The intervention Repetitive
will be Transcranial
Repetitive Magnetic
Transcranial Stimulation (rTMS) is
Magnetic a non-invasive brain
Stimulation. stimulation
Each patient technique. The
will receive investigators will use
active a MagPro R30 with
stimulation the Cool-B80 figure-
targeting the of-eight coil
left dorsolateral (MagVenture, Falun,
prefrontal Denmark).
cortex (lDLPFC) Other Name: rTMS
with a
frequency of 15
Hz and 100%
of the individual
resting motor
threshold, for a
total of 40
trains (60
stimuli per train,
inter-train
interval of 15
second, total
duration 13
minutes). Each
session will be
repeated
twice/daily for
10 consecutive
days for 2
weeks, during
the continued
treatment
phase.
Following this,
the participants
will receive the
maintenance
intervention of
2 sessions per
week for 3
months (rTMS
follow-up), at
the same
parameters
described
above. Device:
MagPro R30
with the Cool-
B80 figure-of-
eight coil
(MagVenture,
Falun,
Denmark).

Outcome Go to
Measures

Primary Outcome Measures ! :

1. Changes in the Visual Analogue Scale

for Craving (VAS-craving)
[ Time Frame: Baseline, after rTMS
treatment: 2 weeks, 3 months, 6
months ]

A Visual Analogue Scale (VAS) is an

instrument to measure a characteristic
or attitude that is believed to range
across a continuum of values. The
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. The VAS score is
determined by measuring in
millimeters from the left-hand end of
the line to the point that the patient
marks.

2. Changes in the Pathological Gambling

Adaptation of the Yale-Brown
Obsessive-Compulsive Scale (PG-
YBOCS) [ Time Frame: Baseline, after
rTMS treatment: 2 weeks, 3 months, 6
months ]

The Pathological Gambling Adaptation

of the Yale-Brown Obsessive-
Compulsive Scale (PG-YBOCS) is a
10-item clinician-administered
questionnaire that measures the
severity of PG over the past one week.
Scores from 0 (min) to 4 (max) are
assigned according to the severity.
The first set of questions (questions 1-
5) assess urges and thoughts
associated with pathological
gambling, whereas the last five
questions assess the behavioral
component of the disorder. Both single
set scores and total score will be
calculated.

3. Changes in Gambling Disorder

Severity as assessed by Timeline
Follow Back (TLFB)
[ Time Frame: Baseline, after rTMS
treatment: 2 weeks, 3 months, 6
months, 12 months ]

Gambling behavior will be assessed

using the TimeLine Follow Back
(TLFB). TLFB is an interview-based
assessment. Using a calendar,
participants are guided through the
process of recalling and reporting daily
gambling behavior. TLFB provides
measures of gambling episodes per
week, gambling days per week, heavy
gambling days per week.

4. Changes in Gambling Behavior as

assessed by Gambling Symptom
Assessment Scale (G-SAS) Total Score
[ Time Frame: Baseline, after rTMS
treatment: 2 weeks, 3 months, 6
months, 12 months ]

Gambling Symptom Assessment

Scale (G-SAS) is a 12-item self-rated
scale designed to assess gambling
symptom severity and change during
treatment. Each 12-item scale has a
score ranging from 0 - 4 (adjective
anchors for 0 and 4 vary for each
item). All items ask for an average
symptom based on the past 7 days.
Total score ranges from 0 (min) to 48
(max), higher scores indicate higher
severity levels.

Secondary Outcome Measures ! :

1. Changes in the Iowa Gambling Task

(IGT) Performance
[ Time Frame: Baseline, after rTMS
treatment: 2 weeks, 3 months, 6
months ]

The Iowa Gambling Task is a

computerized card game commonly
used to measure risky decision-
making tendencies and sensitivity to
reward and loss. Performance is
calculated on the total net score
results from the subtraction of the
disadvantageous deck choices from
the advantageous deck choices
during the entire test ([C'+D']-
[A'+B']).

2. Changes in Snaith Hamilton

Pleasure Scale (SHAPS) Total Score
[ Time Frame: Baseline, after rTMS
treatment: 2 weeks, 3 months, 6
months ]

The Snaith Hamilton Pleasure Scale

(SHAPS) is a 14-item self-report
scale designed to measure hedonic-
tone/anhedonia. Each item is scored
on a 4-point scale, ranging from 0
(not at all) to 3 (extremely). Sum the
scores from all 14 parameters gives
the SHAPS Total Score which may
range from 0 (min) to 42 (max).

3. Changes in Temporal experience of

Pleasure Scale (TEPS) Total
[ Time Frame: Baseline, after rTMS
treatment: 2 weeks, 3 months, 6
months ]

The Temporal experience of

Pleasure Scale (TEPS) is a 18-item
self-report scale designed to
evaluate individual trait dispositions
in anticipatory and consummatory
pleasure experiences. Each item is
scored on a 6-point scale, ranging
from 1 (extremely false) to 6
(extremely true). Sum the scores
from all 20 parameters gives the
TEPS Total Score which may range
from 20 (min) to 108 (max).

4. Changes in Montgomery-Asberg
Depression Scale (MADRS) Total
[ Time Frame: Baseline, after rTMS
treatment: 2 weeks, 3 months, 6
months] ]

The MADRS is a 10-item scale that

evaluates the core symptoms and
cognitive features of clinical
depression. Each MADRS item is
rated on a 0 to 6 scale. The MADRS
Total score ranges from 0 (min) to 60
(max). Higher MADRS scores
indicate higher levels of depressive
symptoms.

5. Changes in Hamilton Rating Scale

for Anxiety (HAM-A) Total
[ Time Frame: Baseline, after rTMS
treatment: 2 weeks, 3 months, 6
months ]

The HAM-A is a 14-item scale that

assesses anxiety symptoms of
anxiety such as "anxious mood",
"tension" or "fears". Each item is
scored on a 5-point scale, ranging
from 0 (not present) to 4 (severe).
Sum the scores from all 14
parameters gives the HAM-A Total
Score which may range from 0 (min)
to 56 (max).

6. Changes in Profile of Mood States

(POMS), Total Mood Disturbance
Score [ Time Frame: Baseline, after
rTMS treatment: 2 weeks, 3 months,
6 months ]

The profile of mood state (POMS) is

a questionnaire designed to
measure present mood state by a
list of adjectives on a 5-point Likert
scale (0 = not at all; 4 = Extremely)
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. A Total Mood
Disturbance Score may be
calculated by adding the scores for
Tension, Depression, Anger, Fatigue
and Confusion and then subtracting
the score for Vigor.

Eligibility Go to
Criteria

Information from the National Library

of Medicine

Choosing to participate in a study is an

important personal decision. Talk with
your doctor and family members or
friends about deciding to join a study. To
learn more about this study, you or your
doctor may contact the study research
staff using the contacts provided below.
For general information, Learn About
Clinical Studies.

Ages Eligible for Study:

18 Years to 65 Years (Adult, Older Adult)

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

No

Criteria

Inclusion Criteria:

Age 18 - 65;
Current diagnosis of Gambling Disorder,
based on the Diagnostic and Statistical
Manual of Mental Disorder - Fifth Edition
(DSM-5);
Drug-free.

Exclusion Criteria:

Current DSM-V diagnosis of substance use

disorders other than nicotine dependence;
Current DSM-V diagnosis of schizophrenia,
bipolar disorder, or other psychotic
disorder;
Use in the past 4 weeks of any medication
with known pro-convulsant action; or
current regular use of any psychotropic
medications (benzodiazepines,
antipsychotic medications, tricyclic
antidepressants, anti-epileptics, mood
stabilizers);
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;
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, 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;
For female patients:
Pregnancy/breastfeeding.

Contacts Go to
and
Locations

Information from the National Library of

Medicine

To learn more about this study, you or

your doctor may contact the study
research staff using the contact
information provided by the sponsor.

Please refer to this study by its

ClinicalTrials.gov identifier (NCT number):
NCT03336879

Contacts

Contact: Giovanni Martinotti, MD, PhD 0039 0

Contact: Mauro Pettorruso, MD 0039 3