Cracking Addiction: Does BRAIN Stimulation-induced Neuroplasticity Reverse Prefrontal Cortex Hypoactivity in Cocaine and neW stImulanTs addiCtion in Humans? (BRAIN SWITCH)
Phase: NA
Conditions: Cocaine Dependence, Substance Use Disorders, Chemical Addiction, Mental Disorder, Cocaine-Related Disorders, Drug Dependence
Sponsor: ITAB - Institute for Advanced Biomedical Technologies

Protocol Title: Cracking addiction: does BRAIN Stimulation-induced neuroplasticity reverse 
prefrontal  cortex  hypoactivity  in  cocaine  and  neW stImulanTs  addiCtion  in  Humans 
(BRAIN SWITCH)?
Abbreviated title: Transcranial Magnetic Stimulation for Cocaine Addiction
Protocol Number: 1496
Date of Approval: June 29, 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
1

Accountable 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
2

A. Précis
Background: Cocaine use disorder (CUD) are a major public health concern, associated with 
high relapse rates, significant disability and substantial mortality. In Italy, it has been recently 
estimated that up to 4.8% of subjects between the ages of 15-64 have assumed cocaine at 
least once, whereas 1.3% subjects currently have a diagnosis of CUD. Unfortunately, current 
interventions are only modestly effective. Preclinical studies as well as human neuroimaging 
studies have provided strong evidence that the observable behaviors that characterize the 
addiction  phenotype,  such  as  compulsive  drug consumption,  impaired  self-control,  and 
behavioral inflexibility, reflect underlying dysregulation and malfunction in specific neural 
circuits.  These  developments  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.
Objectives: The primary goal of the current study is to investigate the effects of repetitive 
transcranial magnetic stimulation (rTMS) targeting the left DLPFC on cocaine craving. The 
co-primary goal is to investigate rTMS effect on cocaine consumption.  Our secondary goals 
are to evaluate rTMS effects on: (1) mood; (2) cognitive functions. Our exploratory goals are 
evaluating rTMS effects on: (1) BOLD response in DLPFC during tasks known to activate 
this area; (2) resting state functional connectivity between the DLPFC and nodes of the 
executive control networks. 
Study population: Treatment seeking cocaine dependent subjects (N=80), 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) or sham 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 or sham 
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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 CCQ from pre- to post treatment [baseline and after rTMS treatment: 2 weeks, 3 
months, 6 months]; (2) changes in cocaine consumption as measured by TLFB self-reports 
and urine drug screen from pre- to post treatment [baseline and after rTMS treatment: 2 
weeks, 3 months, 6 months]. Our secondary outcomes are: Changes in the scores on the  90 
Symptoms Questionnaire (SCL-90) from pre- to post treatment [baseline and after rTMS 
treatment: 2 weeks, 3 months, 6 months]; (2) 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]; (3) changes in the scores on the Hamilton Anxiety 
Rating Scale (HARS); (4) changes in the scores  on the  frontal assessment battery (FAB), 
and on the Flanker task from pre- to post treatment [baseline and after rTMS treatment: 2 
weeks, 3 months, 6 months];
(5) 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];
In addition, in order to investigate DLPFC engagement by TMS, the following exploratory 
outcomes will be analyzed: (1) DLPFC BOLD signal change in response to cocaine-related 
stimuli from baseline to each timepoint [baseline and after rTMS treatment: 2 weeks, 3 
months] (2) Change in resting state functional connectivity, from baseline to each timepoint 
(z-score) [baseline and after rTMS treatment: 2 weeks, 3 months].
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B. Background
Cocaine use disorders
Cocaine use disorder (CUD) are a major public health concern, associated with high relapse 
rates, significant disability and substantial mortality. In Italy, it has been recently estimated 
that up to 4.8% of subjects between the ages of 15-64 have assumed cocaine at least once, 
whereas  1.3%  subjects  currently  have  a  diagnosis  of  CUD.  Unfortunately,  current 
interventions are only modestly effective. Preclinical studies as well as human neuroimaging 
studies have provided strong evidence that the observable behaviors that characterize the 
addiction  phenotype,  such  as  compulsive  drug consumption,  impaired  self-control,  and 
behavioral inflexibility, reflect underlying dysregulation and malfunction in specific neural 
circuits.  These  developments  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-
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, 
5

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.  
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 CUD. 
C. Study Overview
This  is  a  between-subject  double-blind,  randomized,  sham-controlled  study  with  a  1:1 
allocation into two parallel arms: 15 Hz, or sham rTMS stimulation. Participants will be 80 
6

treatment-seeking patients, between the ages of 18-65, who meet diagnostic criteria for CUD 
(moderate to severe). 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 cocaine use disorder (from moderate to severe), based on the 
Diagnostic and Statistical Manual of Mental Disorder – Fifth Edition (DSM-5);
3. Abstinence from cocaine for at least 48 hrs.
Exclusion criteria
1. Current DSM-5 diagnosis of substance use disorders other than nicotine Current DSM-V 
diagnosis of moderate to severe alcohol use disorders 
2. Current DSM-5 diagnosis of schizophrenia, bipolar disorder, or other psychotic disorder; 
3. 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);
4. 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;
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5. Any personal or family history (1st degree relatives) of seizures other than febrile 
childhood seizures;
6. 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;
7. For female patients: Pregnancy/breastfeeding. 
8. Subjects who have contraindications to MRI. Some of the exclusions are:
a.
Have non-MRI compatible metal in the body, such as a cardiac pacemaker, brain 
stimulator, shrapnel, surgical metal, clips in the brain or on blood vessels, cochlear 
implants, artificial heart valves or ferromagnetic fragments in the eye or oral 
cavity as these make having an MRI unsafe.
b. Unable to lie flat on the back for the expected length of the experiment (50 
minutes).
c.
Have an abnormality on the brain imaging or neurologic examination not related 
to the diagnosis.
d. Uncomfortable being in a small space for the expected length of the experiment 
(50 minutes).
e.
Non-removable body piercing or tattoo posing MRI risk
f.
Pregnancy (urine pregnancy test)
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
8

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 
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 
cocaine-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  cocaine 
use/substance abuse 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 (active or placebo) and cocaine-cues exposure
6. HR/PB monitoring
7. VAS cocaine craving 
8. Side effects questionnaire and PANAS
9

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. 
The sham condition will match the number of pulses delivered during the 15Hz session and 
will use the same coil placement but the intensity of stimulation will be set a 3% of the 
individual resting motor threshold so to ensure that the participant will feel similar scalp 
sensations experienced by participants receiving active rTMS, but brain tissue will not be 
stimulated. rTMS will be used with the software necessary for the operator to remain blind to 
the stimulation condition. Also, the software will be pre-programmed by a staff member that 
will not be involved in data collection and analysis. 
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. 
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 
10

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.  
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).
Research MR 
Since pregnancy is an exclusion criterion for MRI, women of child-bearing potential 
must have a negative urine pregnancy test before each MRI procedure. Pregnancy testing will 
be done within 24 hours of each MRI session.
MRI will be conducted on a Philips Achieva 3.0 T scanner (Philips Medical Systems, 
Best, The Netherlands) using a standard body coil transmission and an eight channel SENSE 
head coil reception. T2*-weighted, BOLD images will be acquired with single shot, gradient 
echo (GRE), echo-planar imaging (EPI). During the scan, the subject will hear a thumping or 
buzzing sound.  Earplugs or MRI-compatible headphones will be provided to all individuals. 
Earplugs will be inserted by trained NIH staff. Under the present protocol, total time in the 
scanner  will  be  no  more  than  60  minutes.  We  may  also  record blood  pressure,  skin 
11

conductance, skin temperature, and respiratory rate during the experiment with devices and 
systems that are compatible with the MRI environment.
During the scan, we will first collect structural data. Subsequenly, we will collect resting state 
functional MRI (rs-fMRI). Participants will be asked to keep their eyes closed and not think 
of anything in particular. Resting state FC data will be acquired during 2 blocks of 6 minutes 
each. Finally, subjects will perform two tasks, in a randomized order.  In the cue reactivity 
task, a set of 60 cocaine-related cues and 60 neutral images will be presented and subjects 
will be asked to attend them. The continuous performance task (CPT), a task suitable for 
sustained attention\executive control measure, will be realised by means of visual stimuli 
previous used by our group in a population of psychiatric patients. 
The stimuli will be projected onto a screen via a projector. Subjects will be able to view the 
images via a mirror placed above their head in the scanner. Participants will remain in contact 
with the experimenters at all times via an intercom system built into the scanner. 
Side effects: People are at risk for injury from the MRI magnet if they have pacemakers or 
other implanted electrical devices, brain stimulators, aneurysm clips (metal clips on the wall 
of a large artery), metallic prostheses (including metal pins and rods, heart valves, and 
cochlear implants), permanent eyeliner, implanted delivery pump, or shrapnel fragments. 
Welders and metal workers are also at risk for injury because of possible small metal 
fragments in the eye of which they may be unaware. 
Risk Minimization: The patients are screened using the NMR center safety screening form 
prior to the study and will not receive an MRI scan if the screen is positive.  Women who are 
pregnant may not undergo a research MRI.   All women of childbearing potential will have a 
pregnancy test performed, which must be negative, before proceeding. Individuals with fear 
of confined spaces may become anxious during an MRI. There are no known long-term risks 
or consequences of MRI scans. The length of scan varies from 45 min to 120 min maximum
Questionnaires and Rating Scales
 
-
Adult ADHD Self-Report Scale (ASRS): This questionnaire is an 18-item checklist 
designed by the World Health Organization (WHO) and Workgroup on Adult ADHD 
to determine whether a participant is suffering from symptoms related to attention-
deficit/hyperactivity disorder. Completion time: ~ 5 minutes.
-
TMS Safety Screen:  A questionnaire that aids in determining appropriateness of 
administering TBS. Completion time: < 5 minutes.
12

-
Toronto Alexithymia Scale (TAS-20): A 20-item self-report questionnaire to assess 
emotional awareness. Completion time: ~ 10 minute.
-
Cocaine Craving Questionnaire (CCQ): This measure includes 45 items that measure 
current craving for cocaine. Completion time: ~ 10 minutes.
-
Sensation Seeking Scale V (SSS-V, 127): A 40-item self-report questionnaire that 
assesses individual differences in sensation seeking. Completion time: < 10 minutes.
-
Cocaine Selective Severity Assessment (CSSA): to measure cocaine withdrawal signs 
and symptoms. Completion time minutes: ~ 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 (HARS): 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.
-
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.
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-
Quality of Life Enjoyment and Satisfaction Questionnaire – Short Form (Q-LES-Q-
SF): A self-report scale designed to measure social ties between the participants and 
their friend, family, co-workers, etc. 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. 
-
Columbia-Suicide  Severity  Rating  Scale  (C-SSRS):to  assess  suicidality  ideation. 
Completion time: < 5 min.
-
Brief Psychiatric Rating Scale (BPRS- brief version): to assess psychiatric symptoms. 
Completion time: 15 min.
-
Visual Analogical  Scale for Food Craving (VAS food): to assess food craving. 
Completion time: ~ 5 min.
-
Insomnia severity index (ISI): to evaluate sleep patterns and quality. Completion time: 
~ 3 min.
-
Symptom Checklist-90-R (SCL-90-R): brief self-report psychometric instrument to 
evaluate a broad range of psychiatric symptoms and to measure the progress and 
outcome of psychiatric and psychological treatments. Completion time: ~ 15 min.
Executive and 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. Executive Function and Cognitive Assessment include: 
-
Frontal  Assessment  Battery  (FAB):  to  assess  frontal  dysexecutive  phenotype. 
Completion time: ~ 10 min.
-
Eriksen Flanker Task (Flanker): to assess the ability to suppress responses that are 
inappropriate in a particular context. Completion time: ~ 15 min.
-
Iowa Gambling Task: to assess decision-making process. Completion time: ~ 15 min.
E. Study Design
The study itself will consist of three phases.
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(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 CUDs.
During this phase, treatment response will be assessed by evaluating cocaine craving and 
consumption, psychiatric and medical symptoms and functioning. 
(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 or sham 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 cocaine craving. The 
co-primary goal is to investigate rTMS effect on cocaine consumption.  
Secondary: Our secondary goals are to evaluate rTMS effects on: (1) mood; (2) cognitive 
functions. 
Exploratory: Our exploratory goals are evaluating rTMS effects on: (1) BOLD response in 
DLPFC during tasks known to activate this area; (2) resting state functional connectivity 
between the DLPFC and nodes of the executive control networks. 
Outcomes measures: Our primary outcomes will be: (1) change in craving score as measured 
by the CCQ from pre- to post treatment [baseline and after rTMS treatment: 2 weeks, 3 
months, 6 months]; (2) changes in cocaine consumption as measured by TLFB self-reports 
and urine drug screen from pre- to post treatment [baseline and after rTMS treatment: 2 
weeks, 3 months, 6 months]. Our secondary outcomes are: Changes in the scores on the  90 
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Symptoms Questionnaire (SCL-90) from pre- to post treatment [baseline and after rTMS 
treatment: 2 weeks, 3 months, 6 months]; (2) 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]; (3) changes in the scores on the Hamilton Anxiety 
Rating Scale (HARS); (4) changes in the scores on the frontal assessment battery (FAB), and 
on the Flanker task from pre- to post treatment [baseline and after rTMS treatment: 2 weeks, 
3 months, 6 months];
(5) 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];
In addition, in order to investigate DLPFC engagement by TMS, the following exploratory 
outcomes will be analyzed: (1) DLPFC BOLD signal change in response to cocaine-related 
stimuli from baseline to each time point [baseline and after rTMS treatment: 2 weeks, 3 
months]. (2) Change in resting state functional connectivity, from baseline to each time point 
(z-score) [baseline and after rTMS treatment: 2 weeks, 3 months].
1. Aims
Primary aim:
To determine the effects of rTMS on cocaine craving and consumption in patients with CUD. 

Changes in CCQ score between the active rTMS and sham group, and from pre- to 
post treatment [baseline and after rTMS treatment: 2 weeks, 3 months, 6 months];

Percent of negative urine samples between the active rTMS and sham group, and from 
pre- to post treatment [baseline and after rTMS treatment: 2 weeks, 3 months, 6 
months].
Secondary aims: 

Changes in the scores on the 90 Symptoms Questionnaire (SCL-90) 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 (HARS); 
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
Changes in the scores on the  frontal assessment battery (FAB), and on the Flanker 
task from pre- to post treatment [baseline and after rTMS treatment: 2 weeks, 3 
months, 6 months];

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];
Exploratory aims:

DLPFC BOLD signal change in response to cocaine-related cues from baseline to 
each time point, and between the active and sham group;

Changes in resting state functional connnectivity between the DLPFC and other nodes 
of the executive control network (ECN), from baseline to each time point, and 
between the active and sham group.
Statistical Analysis
Behavioral measures on each of the cognitive tasks as well as questionnaire data from 
each of the experimental conditions will be compared both within and between experimental 
groups using 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). 
The imaging data will be pre-processed and analyzed with MatLab. All functional images 
will be directly registered upon high resolution MPRAGE anatomical scans obtained during 
the same imaging session. Location and intensity of activations from individual and/or 
grouped  data  will  be  translated  into  3D  stereotaxic  coordinates.  Functional  images  of 
activation-induced BOLD signal changes  will  be determined  using cross correlation  or 
multiple regression analyses. Differences in structural and functional measures between 
active rTMS and sham participants will be assessed using between group comparisons (e.g., 
independent samples t-tests). Correlation and multiple regression approaches will be used to 
test  for  an  association  between  clinical  assessment  measures  and  task-specific  neural 
17

measures (e.g., correlation between cocaine craving scores and neural activation in the 
striatum). 
Real vs Sham rTMS Power Analysis.  Because no sham-controlled studies have been 
performed  assessing  the  chronic  effects  of  rTMS  administration  on  behavioral  or 
neurophysiological measures in patients with CUD, anticipating an effect size is difficult. 
However,  open  label  studies  have  shown  substantial  behavioral  changes  in  clinical 
populations and could have similar effects in reducing cocaine use. In order to capture a 
reliable effect while not committing a type II error, a medium-large effect size (Cohen’s d = 
0.65) will be used to calculate the necessary participants to compare real and sham iTBS 
treatments. Approximately 30 participants per group will be required to detect significant 
differences between these two independent groups at a nominal α level of 0.05 in a one-tailed 
t-test assuming a medium-large effect size. We anticipate approximately 80-85% retention 
rate at visit 24, based on previous studies conducted in similar patient populations by our 
group. Therefore, 80 participants will be recruited at baseline, 40 for real and 40 for sham 
iTBS, to acquire the necessary 30 participants in each group for analysis.
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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 80 patients (40 per rTMS and 40 per sham-
stimulation). The distribution will be generated randomly to allow for an equitable age and 
sex distribution.
Double-blind procedure:  rTMS will be used with the software necessary for the operator to 
remain blind to the stimulation condition. Also, the software will be pre-programmed by a 
staff member that will not be involved in data collection and analysis. The sham condition 
will match the number of pulses delivered during the 15Hz session and will use the same coil 
placement but the intensity of stimulation will be set a 3% of the individual resting motor 
threshold so to ensure that the participant will feel similar scalp sensations experienced by 
participants receiving active rTMS, but brain tissue will not be stimulated.
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.
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