Clinical trial NCT02208466
Conditions: Stroke Motor Function
Keywords: repetitive transcranial magnetic stimulation rTMS TMS fluoxetine
Sponsor: Spaulding Rehabilitation Hospital
Start date: 2014-09-01; Completion date: 2019-06-25
Enrollment: 44 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
In this study investigator's aim to assess the effect of a type of non-invasive brain stimulation technique called repetitive transcranial magnetic stimulation (rTMS) in conjunction with fluoxetine on motor recovery after stroke.

Detailed description:

Arms: arm 1: Subjects in this arm will undergo 10 daily sessions over 15 days of active low-frequency rTMS with each session lasting 20 minutes. This will be followed by 8 weekly sessions of active low-frequency rTMS with each session lasting 20 minutes. Additionally, during this time beginning with enrollment, subjects will also be taking 20mg of active fluoxetine by mouth daily. arm 2: Subjects in this arm will undergo 10 daily sessions over 15 days of sham low-frequency rTMS with each session lasting 20 minutes. This will be followed by 8 weekly sessions of sham low-frequency rTMS with each session lasting 20 minutes. Additionally, during this time beginning with enrollment, subjects will also be taking 20mg of active fluoxetine by mouth daily. arm 3: Subjects in this arm will undergo 10 daily sessions over 15 days of sham low-frequency rTMS with each session lasting 20 minutes. This will be followed by 8 weekly sessions of sham low-frequency rTMS with each session lasting 20 minutes. Additionally, during this time beginning with enrollment, subjects will also be taking 20mg of placebo fluoxetine by mouth daily.
Interventions: intervention 1: Active Repetitive Transcranial Magnetic Stimulation (rTMS) intervention 2: Fluoxetine intervention 3: Sham repetitive transcranial magnetic stimulation (rTMS) intervention 4: Placebo Fluoxetine
Intervention descriptions: intervention 1: Subjects will undergo active low-frequency rTMS (1Hz continuous). Each session will last 20 minutes and will be conducted at 100% of the motor threshold. intervention 2: Subjects will receive active fluoxetine (20mg) and take orally consecutively for 90 days. intervention 3: Subjects will undergo sham low-frequency rTMS (using sham coil). This session will last 20 minutes, just as the active session would, however, no magnetic pulses will be delivered. intervention 4: Subject will receive placebo fluoxetine (sugar pills) and will take orally consecutively for 90 days.

Protocol documents:
Prot_SAP_000.pdf: 
Detailed Protocol 1 
ORGANIZATION OF DETAILED PROTOCOL 
 
Title: Effects of contralesional repetitive magnetic stimulation combined with fluoxetine on 
motor recovery in stroke patients 
Protocol #:2014P001046 
Date: 08/10/2017 
 
I. 
BACKGROUND AND SIGNIFICANCE 
 
Overview/summary: This proposal is a NIH R21 sponsored study with the goal to investigate the 
effects of repetitive transcranial magnetic stimulation (rTMS) combined with pharmacotherapy 
(fluoxetine) in the rehabilitation of post-stroke subjects. This research will help to reveal the 
relationship between function restorations via pharmacological intervention when combined with 
noninvasive neuromodulation in patients after ischemic stroke. Stroke is the leading cause of 
disability in the United States (Nowak et al., 2009) According to the American Heart Association, 
over 795,000 people experience stroke annually in the USA (Lloyd-Jones et al., 2009). 
Unfortunately, restitution of post-stroke motor function is frequently incomplete, with the majority 
of stroke patients unable to perform professional duties or activities of daily living by six months 
after their stroke (Hummel and Cohen, 2006). Currently, there are only a few treatments available 
to improve motor function in stroke; most of them are based on motor learning strategies. Although 
these treatments may improve motor function significantly, their effects are often limited. The 
general objective of this research project is to assess the clinical and neurophysiological properties 
of rTMS and fluoxetine to promote motor recovery in post-stroke subjects as indexed by clinical 
motor function scales. This will be done by delivering low-frequency rTMS over the brain primary 
motor cortex (M1) in the unaffected hemisphere while the subjects are receiving fluoxetine 
treatment, subjects will be assessed at one and three months post intervention. Finally, we will 
investigate the mechanisms of this treatment by studying the induced neurophysiological and 
functional 
changes. 
This 
will 
be 
indexed 
by 
motor 
evoked 
potentials, 
cortical 
excitability/inhibition measurements, transcallosal inhibition evaluation, and paired associative 
stimulation. Regarding assurance of success, this proposal has two main specific aims: Aim 1: To 
determine whether low- frequency rTMS associated with fluoxetine offers additional benefits on 
motor rehabilitation and retention of motor skills, than pharmacotherapy alone. Aim 2: To 
determine the effects on cortical excitability when rTMS is combined with pharmacotherapy, 
whether fluoxetine is capable to induce positive or negative effects in M1 neuromodulation. 
 
 
Significance: 
Stroke is a leading cause of disability in the United States (Nowak et al., 2009). According to the 
American Heart Association, over 795,000 people experience strokes annually in the USA, with 
185,000 presenting as recurrent strokes (Lloyd-Jones et al., 2009). Moreover, every 40 seconds-, 
at least one person in the United States suffers from a stroke (Lloyd-Jones et al., 2009). 
Unfortunately, restitution of post-stroke motor function is frequently incomplete, with the majority 
of stroke patients unable to perform professional duties or activities of daily living by six months 
after their stroke (Hummel and Cohen, 2006).  
 Currently there are only a few treatments available to improve motor function in stroke, most of 
which are based on motor learning strategies. Although these treatments may improve motor 


Detailed Protocol 2 
function significantly, their effects are often limited, possibly due the lack of skill consolidation. 
Herein we propose to enhance the effects of post-stroke motor rehabilitation using a powerful 
noninvasive technique of brain modulation, repetitive transcranial magnetic stimulation (rTMS), 
in combination with the serotonergic agent fluoxetine to modulate cortical plasticity and facilitate 
motor restoration. 
 
Neuroimaging analyses of stroke subjects have demonstrated critical post-morbid aberrances in 
cortical excitability in the intact primary motor cortex (M1) of the unaffected hemisphere (Hummel 
and Cohen, 2006).This increased cortical excitability has been noted to correspond with 
movements of the paretic arm in patients with motor impairment (Ward et al., 2003), (Calautti and 
Baron, 2003). In addition, the level of cortical excitability of the intact hemisphere directly 
correlates with the degree of paresis in the affected extremity (Hummel and Cohen, 2006). Lastly, 
post-stroke subjects exhibited changes in motor cortical excitability and abnormal levels of 
interhemispheric inhibition from the unaffected to the affected motor cortex (Hummel and Cohen, 
2006).These four observations have helped orchestrate several theories: (1) that there is 
maladaptive interhemispheric competition after stroke which worsens hand paresis, and (2) that 
modulation can improve motor function (Hummel and Cohen, 2006). 
 
Repetitive Magnetic Stimulation improves motor function in stroke subjects: 
Recent studies have demonstrated that cortical brain stimulation with invasive and non-invasive 
brain stimulation improves motor function in stroke patients. An animal and a human study have 
indicated that epidural stimulation of the motor cortex results in motor function enhancement after 
stroke (Plautz et al., 2003, Brown et al., 2003, Brown et al., 2006). Furthermore recent clinical 
trials have demonstrated that motor cortex stimulation with noninvasive techniques such as 
repetitive transcranial magnetic stimulation (rTMS) can also enhance motor function in stroke 
patients. Beneficial effects on motor function can be induced, as shown by our recent clinical trials, 
with either inhibitory 1-Hz rTMS (Mansur et al., 2005) and cathodal-tDCS (Fregni et al., 2005a) 
of the contralateral, unaffected hemisphere or excitatory 3-Hz rTMS (Khedr et al., 2005) and 
anodal-tDCS (Hummel et al., 2005, Fregni et al., 2005a) of the affected hemisphere. In a recent 
review with 50 studies on noninvasive brain stimulation of motor cortex to modulate motor 
function, there was a significant pooled effect size towards improvement of motor function; 
however these effects were small and short-lived (Adeyemo, 2012). Here we propose to enhance 
further these effects by combining rTMS with a serotoninergic agent. 
 
Pharmacologically induced motor recovery in stroke : 
Studies have suggested that serotonergic agents fluoxetine and citalopram have a positive effect 
on motor function in hemiplegic patients after stroke. (Dam et al., 1996, Zittel, Weiller, and Liepert 
2008; Pariente et al., 2001; Gainotti et al., 2001). While the drugs’ effect on mood or motivation 
may be responsible for some of this effect, Acler et al.(2009) found that citalopram decreased 
contralesional motor cortex excitability as recorded by transcranial magnetic stimulation, 
suggesting a specific effect on motor systems, and Pariente et al., (2001) confirmed this when they 
found hyperactivation in the ipsilesional primary motor cortex on fMRI in 8 patients during 
fluoxetine administration.  Recently Chollet et al., 2011, in a randomized controlled trial of 118 
ischemic stroke patients – the FLAME trial - concluded on the basis of changes in the Fugl-Meyer 
Motor Scale scores that motor recovery is enhanced by fluoxetine compared to placebo in 
combination with usual rehabilitation therapy. 


Detailed Protocol 3 
 
Sponsors: 
NIH 
 
II. 
INNOVATION 
 
On the one hand, it has been recognized physically and biologically the influence an induced 
magnetic pulse has in excitable tissue, on the other hand, pharmacological induction of motor 
recovery is gaining more attention and the mechanisms behind such properties are being gradually 
understood. It seems plausible to combine the mechanistic properties of both therapeutic 
approaches, in order to add synergism in their effects on neuromodulation and function restoration. 
The idea of combining both therapies comes from our recent trial coupling the use of noninvasive 
brain stimulation with sertraline (another SSRI) for the treatment of depression. In this relatively 
large trial with 120 subjects, we showed that noninvasive brain stimulation plus sertraline has a 
synergistic effect as compared with sertraline alone or noninvasive brain stimulation alone 
(Brunoni, 2012). The hypothesis is that because rTMS has its main effect via top-down 
mechanisms and fluoxetine via bottom up mechanisms (see figure 1), then combination of both 
therapies may enhance the effects when compared to fluoxetine alone. This research project is 
proposing a new perspective for the treatment of motor deficits in stroke subjects. On one hand, 
we are taking into account the network properties for learning and consolidation and understanding 
how to modify them by balancing interhemispheric connectivity using low-frequency rTMS in a 
top-down stimulation; and on the other we are modulating the restorative mechanism associated 
with fluoxetine in a bottom-up fashion, see figure No. 1 
 
Figure 
1 
, 
Schematic 
representation 
of 
neuromodulatory 
mechanisms 
on 
motor 
recovery. rTMS at 1Hz over unaffected M1 will 
regulate 
interhemispheric 
inhibition, 
while 
fluoxetine will provide bottom-up regulation  
throughout subcortical pharmacological effects 
(selective 
neurotransmitter 
interaction 
and 
possibly promoting trophic factors expression). 
Modified from Fregni et al. 2007   
 
 
 
III. 
SPECIFIC AIMS 
 
This research will generate knowledge regarding stroke motor rehabilitation, including potential 
strategies to help coordinate assessments and treatment protocols in the future. For this population, 
this is extremely important as several critical facts should be considered: (i) Existing treatments, 
such as traditional physical or occupational therapy still underestimate the role of brain cortical 
modulation in motor recovery processes; (ii) As this population ages, and lack of function 
perpetuates abnormal motor patterns, inner mechanisms of brain plasticity becomes less available, 
and progressive physical symptomatology (such as spasticity or arthrosis) becomes more prevalent 
and exasperates abnormal function; and (iii) A primary reason for the lack of efficacy of current 


Detailed Protocol 4 
treatments is that current therapeutic approaches do not take into account the mechanisms 
underlying motor re-organization in this condition. In fact, evidence indicates that abnormal 
cortical motor plasticity (maladaptive) is a phenomenon related to significant reorganization at 
different levels of the neuroaxis, particularly at the motor cortex and within the hemispheres. For 
these reasons, it is important to guide therapeutic approaches towards functional neuroplasticity. 
In this context the combination of brain stimulation with endogenous pharmacological modulation 
may be a profitable strategy to improve functional outcomes in stroke motor rehabilitation. 
 
Given that rTMS has its direct effect on cortical areas; secondary modulation of subcortical neural 
networks is established via top-down mechanisms. Therefore, combining rTMS with other 
approaches that can modulate primarily subcortical systems such as the selective serotonin 
reuptake inhibitors (SSRIs) may result in a synergistic benefit on the motor system. Based on the 
recent results of the multicenter trial assessing fluoxetine for stroke recovery (FLAME study) and 
our recent large factorial trial testing the combination of non-invasive brain stimulation with 
sertraline for the treatment of depression (Brunoni et al, 2013), we will test the hypothesis that 
rTMS will enhance further the effects of fluoxetine on neuroplasticity and consequently motor 
function. We will evaluate cortical plasticity using single and paired pulse TMS including the 
following assessments; paired associative stimulation (PAS), intracortical inhibition and 
facilitation, cortical silent period, and transcallosal inhibition; and motor function as to grade the 
impact of the proposed interventions on motor performance. The specific aims of this study, which 
seeks to recruit 45 subjects, are to; 
 
Aim 1: Determine whether low-frequency rTMS of the unaffected M1 associated with fluoxetine 
offers an additional benefit on motor function over pharmacotherapy (fluoxetine) alone after three 
months of the combined therapy. Our hypothesis is that low-frequency rTMS combined with 
fluoxetine will induce greater improvement in motor function as compared to sham rTMS and 
fluoxetine. 
 
Sub Aim 1.1: As to control for the effects of spontaneous recovery, we will also assess whether 
the superior effects of the combined effects will be superior to spontaneous recovery by comparing 
the results of the two groups against a placebo group (placebo fluoxetine and sham rTMS). We 
hypothesize that both groups (combined treatment and fluoxetine alone) will have a superior effect 
as compared to placebo only. 
 
Aim 2:  Determine whether fluoxetine combined with rTMS results in additional positive 
modulation of motor cortex excitability and cortical plasticity as compared to fluoxetine alone. 
Our hypothesis is that active rTMS combined with fluoxetine will induce a greater increase in the 
amplitude of motor evoked potential and greater LTP-like (long-term potentiation) as indexed by 
PAS-25 of the affected hemisphere (M1) as compared to sham rTMS combined with fluoxetine. 
 
 
IV. 
MEDICAL MONITOR 
 
 
Medical Monitor:   
Nevena Zubcevik, DO 
Professor, Department of Physical Medicine and 


Detailed Protocol 5 
Rehabilitation, Harvard Medical School 
 
The principal investigator will be available during the course of each study session. 
 
The medical monitor is required to review all unanticipated problems involving risk to subjects or 
others, serious adverse events and all subject deaths associated with the protocol and provide an 
unbiased written report of the event.  At a minimum, the medical monitor must comment on the 
outcomes of the event or problem and in case of a serious adverse event or death, comment on the 
relationship to participation in the study.  The medical monitor must also indicate whether he/she 
concurs with the details of the report provided by the principal investigator.  This person must also 
be available by pager during the course of each study session. 
 
 
V. 
SUBJECT SELECTION 
 
We will recruit 45 patients with ischemic stroke. The desired sample size is calculated, with some 
assumptions, based on the amount of patients treated in Spaulding Rehabilitation Hospital and 
affiliate hospitals and clinics. The study eligibility criteria that will be used for this study are based 
on the FLAME trial (as we will investigate the additional benefits of combining fluoxetine with 
rTMS). We broadened the motor score criteria and time since stroke in order to significantly 
improve the impact of the study and improve our understanding of the mechanisms behind 
plasticity after stroke in a broad population.  
 
Subjects will conform to the following criteria: 
 
 
Inclusion Criteria: 
• Ischemic infarction within the past 2 years post event that has caused hemiparesis or 
hemiplegia, as self-reported and/or confirmed by medical record.  
• Older than 18 years old.  
• Upper extremity weakness defined as a score of >11 and ≤56 on the arm motor Fugl-Mayer 
motor scale.  
• Minimal pre-stroke disability defined as a score of <3 in the Modified Rankin Scale.  
• Subjects need to be able to follow directions and participate in 2 hours of testing with short 
breaks. 
• Subjects need to be able to provide informed consent.  
 
Exclusion Criteria: 
• Any substantial decrease in alertness, language reception, or attention that might interfere 
with understanding instruction for motor testing 
• Excessive pain in any joint of the paretic extremity (not applicable to severe stroke 
subjects), as self reported 
• Contraindications to single pulse TMS (will be used to measure cortical excitability) such 
as: history of seizures, unexplained loss of consciousness, any metal implants in the head, 
frequent or severe headaches or neck pain, any other electronic implanted medical devices 
such as pacemakers, defibrillators, or implant medication pump. 


Detailed Protocol 6 
• Patients who are currently taking fluoxetine should accept a 5 week washout period before 
baseline (to be reconfirmed during baseline visit). 
• Patients taking any other SSRI at the time of enrollment or in the previous month (the 
patients should accept a 5 week washout period before baseline - to be reconfirmed during 
baseline visit).  
• Patients taking any other medication likely to have adverse interaction with SSRIs (all the 
medications the patient is taking will be carefully reviewed, as noted below in “Monitoring 
of important drug interactions”). 
• Active depression on admission to SRH defined by a score of 24 or higher in the Hamilton 
Depression Rating Scale (HAM-D) 
• Concurrent medical condition likely to worsen patient’s functional status in the next 6 
months such as: cancer, terminal heart, kidney or liver disease, as self-reported and/or 
confirmed by medical record.  
• Pregnancy.  
 
 
Exclusion of Pregnancy in the Study: 
The decision to exclude pregnant women is based on the current guidelines stated in “Safety, 
ethical considerations, and application guidelines for the use of transcranial magnetic stimulation 
in clinical practice and research” by Rossi et al. 2009, of which the principal investigator of this 
study, Dr. Felipe Fregni is one of the authors.  There is no specific recommendation for or against 
pregnancy. However since this study will be utilizing Repetitive TMS as a mode of intervention, 
we will take the conservative approach and exclude pregnancy.  Female subjects of child bearing 
potential will be asked to take a pregnancy test. If the pregnancy test is positive, the subject may 
not enroll in the study. We will also perform a pregnancy test weekly to all female subjects of 
childbearing age   
 
Monitoring of important drug interactions: 
We will be monitoring for any drugs the patient might be taking that may have interactions with 
fluoxetine. Since fluoxetine is a potent inhibitor of CYP2D6 and CYP3A4, drugs metabolized by 
these enzymes should be avoided or dosage should be modified. Mainly, fluoxetine should also 
be avoided in combination with any drugs that have increase risk of serotonin syndrome or QT- 
interval prolongation.   
Prior to patients enrollment, the licensed physicians collaborating with the study – Dr. Black-
Shaffer - will perform a close review of the medications the patient is receiving while inpatient in 
SRH or as an outpatient. They will determine if any drug the patient is taking has any possible 
interactions with fluoxetine. If needed and if possible, dose adjustments of these medications will 
be made. A log of the medications the patient is taking will be kept and patients will be asked to 
inform the study staff if any changes have been made in the medications or in the dosage. Study 
staff will otherwise confirm with subjects weekly that no changes have been made. 
 
 
 
 
VI. 
SUBJECT ENROLLMENT 
 


Detailed Protocol 7 
Eligible subjects will be identified at the time of admission to Spaulding Rehabilitation Hospital 
or affiliated hospitals in the Boston area with the diagnosis of ischemic stroke. During the first 
month after the ischemic events they will be screened for inclusion and exclusion criteria and asked 
to be enrolled in the study. Spaulding Rehabilitation Network is the largest rehabilitation provider 
in the New England Area; thus captures most patients in our geographical area. There are 
approximately 500 stroke admissions per year. Patients are referred from Massachusetts General 
Hospital, Brigham and Women’s Hospital, and a variety of other centers in the Boston area and 
beyond. The study staff may contact physicians, clinicians and other health care providers from 
inside and outside Partners Network (such as Massachusetts General Hospital, Brigham and 
Women’s Hospital and Spaulding Rehabilitation Hospital, inpatients or outpatient units) and ask 
for collaboration with recruitment. Their collaboration can include handing out research study 
fliers to patients for recruitment and directly talking with potential ones. Subjects within the 
Partners network may be indentified through medical records systems (such as LMR, Meditech 
and Epic) in conjunction with cooperation from collaborating physicians.  Patients who elect to 
enroll in the Research Patient Data Registry (RPDR) may also be located within the Partners 
Network in collaboration with referring physicians. 
 
Patients can be enrolled as outpatients or inpatients. If patients are enrolled during their inpatient 
condition in SRH and if they are discharged before the ending of the study they will continue their 
enrollment by coming to our lab for visits and taking the medication at home or in any other facility 
they were transferred to. Outpatient subjects may be identified through the SRN or also through 
alternative recruitment methods such as flyers, email, digital signage, internet ads, or newspaper 
ads. We would also like to attend events, such as stroke related conferences, talks, and support 
groups to speak about the study and hand out IRB-approved materials.  
 
When contacting subjects by email, we will communicate through the Partners network as per the 
Partners policy regarding secure email communication.  If the first method of contact with the 
subject is through email, we will explain that they will receive encrypted emails going forward. 
This initial unencrypted email will not contain any PHI or study information, and will have 
instructions on how to open encrypted emails. We will also explain that they have the option to 
opt out of secure emails after informing them of the possible security risks. If they chose this 
option, this preference will be noted in our contact log.  
 
Stimulation sessions with rTMS will be administered to the patients either in SRH while inpatient 
or in our lab if outpatient. The drug will be dispensed by the pharmacy and nursing staff of 
Spaulding while subjects are inpatient at the hospital. Upon discharge from Spaulding subjects 
will be given the remaining pills in their prescribed amount supply and instructed to take one each 
day until finished. If the subject is discharged to a skilled nursing facility a copy of the protocol 
and contact information will be sent with the patient and the medication.  Study staff will call the 
facility to answer questions and enlist support in continuing the study medication there.  Study 
drug compliance will be monitored weekly via self-report measures either during a study visit or 
by phone. Subject’s responses will be kept in a compliance log.   
 
Informed consent will be obtained by a licensed physician or the Principal Investigator   (not 
involved in the patient’s care) at SRH. The subject will meet with the PI or licensed physician, and 
the test procedures will be described and the testing equipment will be shown to the subject. The 


Detailed Protocol 8 
PI or licensed physician will clearly explain all the procedures and risks of the testing outlined in 
the consent form. The subject will be given an hour to consider their decision (if they have not 
received the consent form prior to the screening visit) and will be encouraged to ask questions, 
both during the initial phone interview and throughout the study. The PI or licensed physician will 
answer any questions regarding the study at the time consent is given.  Once enrolled, the subject 
may pause or terminate his/her participation at any time during the study.  
 
 
VII. 
STUDY OVERVIEW AND PROCEDURES  
 
Study overview:   
This study is a parallel, randomized, double blind, placebo controlled clinical trial. We will use 
the same duration and regimen of fluoxetine treatment as the FLAME trial as this trial showed that 
fluoxetine is efficacious when compared against placebo. Subjects will be randomized to one of 
three groups, where they will receive: 1) fluoxetine + active rTMS, 2) fluoxetine + sham rTMS or 
3) sham rTMS + placebo fluoxetine. With a total of 45 patients, 15 patients will be randomized to 
each group using a computer based randomization program. 
 
This study is structured in 3 visits where baseline and post intervention assessments will be 
collected, 10 daily stimulation sessions (from 3rd until 12th visit), and subsequently, subjects will 
return for a weekly stimulation session for the next 8 weeks (visit 14th to 21th). Last visit will be 
the 22nd and the whole battery of assessments is going to be collected. A table of the study flow is 
presented below. 
 
Protocol Details: 
There will be ten stimulation visits (to be given over a period of 15 days), followed by weekly 
sessions of stimulation for the next 8 weeks. During each stimulation visit, rTMS equipment will 
be placed on the subject’s unaffected hemisphere over the primary motor cortex (M1). They will 
receive either active or sham rTMS with fluoxetine – or sham rTMS and placebo. The 30  subjects 
randomized to receive sham  rTMS will have the opportunity to enroll into an open label at the 
conclusion of their participation in the randomized portion of the trial. This will consist of 10 daily 
active stimulation sessions that can be carried out over the course of 2 weeks. Subjects will only 
receive rTMS and not the study drug, Fluoxetine. 
 
Intervention Details: 
 
Repetitive transcranial magnetic stimulation: 
 
Low frequency rTMS stimulation (active stimulation) 
• During this stimulation session, the participant will receive a session of low-frequency 
rTMS to the primary motor cortex of the unaffected cerebral hemisphere. The resting 
motor threshold (MT) of the first dorsal interosseous (FDI) in the affected and 
unaffected hemispheres will be measured. The participants will receive the rTMS over 
the area corresponding to the “hot spot” for stimulation as defined by motor threshold 
determination, as described by prior rTMS application studies (Rossini et al., 1994). 


Detailed Protocol 9 
• Low frequency rTMS stimulation will be applied according to the following parameter: 
intensity of 100% MT, frequency of 1 Hz, 1200 pulses as a single, continuous train 
lasting 20 minutes. This intervention is associated with significant motor gains in 
chronic (Mansur, 2005)(Fregni, 2006) and acute stroke. In addition, it is a safer 
approach to be used in chronic stroke (Fregni review). 
 
Sham rTMS stimulation: 
• For sham rTMS stimulation, we will place the coil in the same location usually used 
for the active stimulation. We will also utilize the same stimulation parameters. 
However, we will replace the active coil with a sham coil to ensure no stimulation is 
actually provided. 
 
Drug Intervention: 
 
Fluoxetine: 
• Subjects will receive fluoxetine 20 mg daily after enrollment during their baseline visit. 
They will take the study drug by mouth once daily from this day  until the protocol is 
completed (for 90 days) - we will use the same regimen as in the FLAME study.  
• The drug will be dispensed by the pharmacy and nursing staff of Spaulding while 
subjects are inpatient at the hospital. Upon discharge from Spaulding subjects will be 
given the remaining pills in their prescribed amount supply and instructed to take one 
each day until finished. 
• If the subject is discharged to a skilled nursing facility a copy of the protocol and 
contact information will be sent with the patient and the medication.  Study staff will 
call the facility to answer questions and enlist support in continuing the study 
medication there. Study drug compliance will be monitored weekly via self-report 
measures either during a study visit or by phone. Subject’s responses will be kept in a 
compliance log.   
• If the subject is enrolled as outpatient a licensed physician on the study staff will 
dispense the medication to the subject during the baseline visit.  
 
Placebo control: 
• Subjects will receive a placebo pill daily after enrollment during their baseline visit. 
They will take the study drug by mouth once daily from this day until the protocol is 
completed (for 90 days). The placebo will be dispensed by the pharmacy and nursing 
staff of Spaulding while subjects are inpatient at the hospital. Upon discharge from 
Spaulding subjects will be given the remaining pills in their prescribed amount supply 
and instructed to take one each day until finished. The procedure for taking the study 
drug and to monitor for compliance will be the same as for the patients receiving the 
active drug.  
 
 
Detailed Study Outline 
 
Screening 


Detailed Protocol 10 
Screening Visit (Visit 1) - (Approx Time: 45 mins) 
 
Screening Procedures: 
At Screening the PI and the co-investigators will conduct a review of inclusion/exclusion criteria 
to determine the subject’s eligibility for enrollment. Study procedures will be reviewed with the 
subject, and documentation of informed consent will be obtained.  
 
At Screening the following procedures will be completed: 
 
• 
Discuss study-specific procedures with the subject  
• 
Review inclusion and exclusion criteria, including list of current medication (for review 
with Dr. Black-Schaffer)   
• 
Obtain a signed and dated consent form. 
• 
Perform a Fugl-Meyer motor scale 
• 
HAM-D (depression scale) 
• 
Modified Rankin Scale (mRS) 
• 
Demographic Data 
• 
Urine pregnancy exam (if applicable) 
 
Randomization: 
Once eligibility and consent have been approved and completed, randomization will occur using 
the randomized list generated by an automatic web-base randomization program 
(www.randomization.com). Subjects will be randomly assigned to one of the three groups 
described in a 1:1:1 allocation ratio. We will use blocks from 3-5 subjects. Randomization order 
will be kept in sealed envelopes; therefore subjects will get their assignment according to the order 
of entrance in the study. The study coordinator will retain the original randomization list which 
will be kept in a locked place. The randomization list will be given to the pharmaceutical company 
compounding the study drug, and copy will be kept locked in the pharmacy in case of necessary 
unblinding. 
If the subject receives sham stimulation, at the end of their participation in the study he/she may 
re-enroll into an open label portion of the study where he/she will receive 10 days of active rTMS 
stimulation over the course of 2 weeks. These data will be used for exploratory analyses only. 
 
 
Visit 2 
Baseline Visit - (Approx Time: 3 hours) 
 
 
In this visit, patients will start receiving the study drug either Fluoxetine or placebo 
Fluoxetine, by mouth, once daily until the protocol is over (90 Days total).  
 
Single and Paired pulse TMS Assessments - A baseline assessment of cortical excitability will 
be performed in this visit, and repeated in Visit 12 and 21. For this we will evaluate the motor 
evoked potential (MEP) and the resting motor threshold (MT) using single pulse TMS. We will 
also used paired-pulse techniques to measure intra- and inter- cortical excitability. Both the 


Detailed Protocol 11 
affected and unaffected M1 will be studied. Baseline assessment of the following will also be 
performed in this visit by a trained co-investigator: 
 
• Jebsen-Taylor Hand Function Test (JTHF) 
• Fugl-Meyer motor scale (FMMS) 
• Modified Ashworth Scale 
• Beck Depression Inventory (BDI) 
• National Institute of Health Stroke Scale (NIHSS) 
• Mini Mental State Examination (MMSE) 
• Visual Analog Scale (VAS) for anxiety 
• Visual Analog Scale (VAS) for pain/comfort 
• Side Effects Questionnaire for rTMS/TMS 
• Side effects Questionnaire for Fluoxetine (to have baseline data) 
Patients will also be asked about how many hours of occupational or physical therapy they are 
receiving and a log will be kept. This log will be updated every week. A log of their current 
medication will also be kept and updated weekly. 
 
 
Visit 3-12 
Daily Stimulation Visits (10 sessions over 15 days) - (Approx Time: 1 hour) 
• During each stimulation session - the subject will receive 20 minutes of either low 
frequency rTMS or Sham rTMS.  
• In each visit they will also answer the rTMS and Fluoxetine side effects questionnaires (in 
the case of unexpected or severe side effects a study physician will be notified immediately. 
Serious adverse events will be reported  in accordance with IRB policies. All other 
expected side effects will be reviewed with the study physician on a monthly basis.) ( 
• We will also update the compliance, therapy and medication logs weekly. 
Visit 13 
Follow Up Visit (Approx Time 3hrs) 
• Jebsen-Taylor Hand Function Test (JTHF) 
• Fugl-Meyer motor scale (FMMS) 
• Modified Ashworth Scale 
• Beck Depression Inventory (BDI) 
• Visual Analog Scale (VAS) for anxiety 
• Visual Analog Scale (VAS) for pain/comfort 
• TMS Assessments 
• Side Effects Questionnaire for rTMS/TMS 
• Fluoxetine side effects Questionnaire 
• Blinding questionnaire 
 
Visits 14-21 
Weekly Stimulation visits - (Approx Time: 1 hour) 
• During each stimulation session - the subject will receive 20 minutes of either low frequency 
rTMS or Sham rTMS. 


Detailed Protocol 12 
• In this visits they will also answer the rTMS and the Fluoxetine side effects questionnaires, 
and the adverse event log (in the case of unexpected or severe side effects a study physician 
will be notified immediately. Serious adverse events will be reported  in accordance with 
IRB policies. All other expected side effects will be reviewed with the study physician on 
a monthly basis.) 
•  
• We will also update the compliance, therapy and medication logs weekly. 
 
Visit 22 
Post- Intervention assessment visit - (Approx Time: 3 hours) 
• Jebsen-Taylor Hand Function Test (JTHF) 
• Fugl-Meyer motor scale (FMMS) 
• Modified Ashworth Scale 
• Beck Depression Inventory (BDI) 
• Mini Mental State Examination (MMSE) 
• Visual Analog Scale (VAS) for anxiety 
• Visual Analog Scale (VAS) for pain/comfort 
• TMS Assessments 
• Side Effects Questionnaire for rTMS/TMS 
• Fluoxetine side effects questionnaire 
• Blinding questionnaire 
 
Study Visit Summary Table: 
Assessments and 
Interventions 
Screening 
(Visit 1) 
Visit 
2 
Visit  
3-12 
 
Visit 
13 
Visit  
14-21 
 
Visit  
22 
 
Review of eligibility criteria  
X 
 
 
 
 
 
 
Demographic Data 
X 
 
 
 
NIHSS 
 
X 
 
 
Modified Rankin Scale 
X 
 
 
 
HAM-D 
X 
 
 
 
Jebsen Taylor Hand Function 
Test (JTHF) 
 
X 
X 
X 
Visual analogue scale (VAS) for 
anxiety 
 
X 
X 
X 
Modified Ashworth Scale   
 
X 
X 
X 
Visual Analogue Scale (VAS) 
for pain/comfort   
 
X 
X 
X 
Mini Mental State Examination 
(MMSE)  
 
X 
 
X 
Fugl Meyer (FM)  
X 
X 
X 
X 
Beck Depression Inventory 
(BDI)  
 
X 
X 
X 


Detailed Protocol 13 
TMS Assessments 
 
X 
X 
X 
STIMULATION 
1. Low-Frequency rTMS + 
fluoxetine OR 
2. Low-Frequency sham  
rTMS + fluoxetine OR 
3. Low-Frequency sham  
rTMS + placebo  
 
 
X 
 
X 
 
Side Effects Questionnaire for 
rTMS (post-stimulation) and for 
fluoxetine 
 
X 
X 
X 
X 
X 
Blinding Questionnaire (post-
stimulation) 
 
 
 
X 
 
X 
Approximate Time 
45 mins 
3 hrs 
1 
hour 
3 hrs 
1 hour 
3hrs 
 
Blinding Procedure: 
 
Participants, family members, treating staff, physicians, data collectors, SRH pharmacists, site 
investigators and the statistician at the lead site will be blinded to group assignment until after the 
final analyses. The lead pharmacist who prepares the study drug kits will be blinded to group 
assignment. Johnson Compounding and Wellness Center, which is responsible for 
manufacturing/delivering the correctly randomized study drug, will be unblinded. When Johnson 
Compounding and Wellness Center sends the medication to SRH for dispensing to the subject, a 
note indicating the contents, “Active” or “Placebo,” will be with the medication. This note will be 
placed in a sealed envelope should the subject’s medication require unblinding to treat an adverse 
event.  
 
Guidelines and Procedures for Breaking the Blind: 
In rare cases, it may be necessary to break the blind to facilitate management of a serious adverse 
event (SAE). At each site, an assigned person (the PI or designee) will have access to unblinding. 
In the vast majority of cases where adverse events are noted, however, the decision about whether 
or not to continue the study drug, and what treatment to provide, if any, can be made without 
knowing whether the patient was receiving study drug or placebo. Since most SAEs might be due 
to something else even if the patient is in the active treatment group, the treating physician should 
assess multiple possible causes of the adverse event and should stop the study drug at least 
temporarily as long as there is some chance that it is responsible for the event. Just as in clinical 
practice, if an adverse event is thought to be due to a given drug, and that drug is stopped, clearance 
of the adverse event tends to support the causal connection. On the other hand, failure of the 
symptoms to resolve with stopping the drug requires the physician to search for alternative causes. 
Thus, in general, the treating physician should make a decision about whether or not an adverse 
event is likely to be connected to the study drug in a blinded fashion, and stop the drug where 
appropriate, at least temporarily. If the adverse event does not resolve, the physician may identify 
another etiology and make a decision, in the future, to restart the study drug. 


Detailed Protocol 14 
In order to meet the criteria for unblinding the following scenario should be true. In uncommon 
instances, the treating physician may feel that it is critical to know which drug the subject is 
receiving, because:  
1. The adverse event is serious; and 
2. It will be potentially harmful or costly to stop the study drug and act simultaneously on 
other possible causes of the adverse event; and 
3. It will be dangerous to stop the study drug and wait for a few days to see whether the 
adverse event resolves before acting on other possible causes. 
 
In all cases, the Treatment Unblinding form, which prompts the PI to address the need to unblind 
to ensure unblinding is indeed necessary, should be completed prior to unblinding the participant. 
Unmasking/unblinding should be considered a serious action. The treating physician may unblind 
the participant if unblinding is considered to be essential to clinical management.  
 
The following questions should be answered on the Treatment Unblinding form by the treating 
physician whenever unblinding is being considered or has been implemented: 
 
1. What is the adverse event that leads you to want to unblind the treatment condition? 
2. What prevents you from addressing all possible causes of the adverse event 
simultaneously? 
3. What prevents you from stopping the study drug blindly and waiting a few days to evaluate 
the course of the adverse event, and then make decisions about other interventions 
accordingly?    
 
In all cases in which unblinding has occurred, the study physician treating the participant has been 
unblinded and will record and maintain these data in a confidential log so the case can be reviewed 
and the reasons for unblinding tracked. The treating physician should be reminded not to reveal 
the treatment assignment to any other staff members unless this information is essential to patient 
management, or to the patient or the patient’s family.  
 
Note: To avoid inadvertent or non-essential episodes of unblinding, the PI (or designee) should 
assure that the covering physician staff, residents, physician’s assistants and nursing staff is 
informed that stringent guidelines must be followed when starting and stopping all medications. 
Unblinding cannot occur unless the Guidelines for Unblinding have been reviewed and completed 
by the PI.  
 
A record of each subjects’ assignment from Johnson Compounding and Wellness Center, “Active” 
or “Placebo,” is placed in a sealed envelope labeled with the Study Name and ID along with the 
subjects name and Study ID Number on the outside. This envelope is placed in a larger envelope 
labeled with the Study Name and ID in the SRH Night Pharmacy Omnicell automated dispensing 
machine. Only SRH Nursing Managers and the SRH IND Pharmacist, using the Omnicell machine 
can access the study envelope using the product identifier “unblinding key 
 
DESCRIPTION OF ASSESSMENTS:   
 
Clinical Assessments: 


Detailed Protocol 15 
A rater blind to the treatment arm will administer the following:  
 
1. Jebson Taylor Hand Function Test (JTHF): This will be our primary outcome. This test 
was designed as a broad measure of hand function. It provides information on the time 
required for the subject to turn cards, pick up small objects, simulate feeding by picking up 
beans with a spoon, stack checkers, and lift empty and 500 g full cans (Jebsen et al., 1969). 
This instrument showed to be sensitive to measure motor changes induced by motor cortex 
stimulation (REVIEW marcel - BJ). When performing a certain sub-task, if the subject 
demonstrates the inability to complete that task and verbally acknowledges he/she cannot 
perform, we will move on to the next task and score appropriately.  
2. Fugl-Meyer motor scale (FMMS): This instrument was the main outcome used in the 
FLAME study and is widely used for assessment of motor recovery after stroke. (Gladstone 
et al, 2002). 
3. Modified Ashworth Scale: This instrument is a 6-point rating scale that is used to measure 
muscle tone. This test is performed by moving the body part through the joint range of 
motion (ROM), with no specification as to the speed of the movement. 
4. Beck Depression Inventory (BDI):  This 21-item multiple-choice test measures the 
presence of and the degree of depression in adults.   
5. Mini Mental State Examination (MMSE): The MMSE is a brief screening instrument used 
to assess cognitive abilities. We will be using this assessment as a baseline evaluation and 
a follow- up. Consistency of MMSE scores should suggest that a subject had no cognitive 
changes throughout the intervention period that may have affected test performance or 
carryover of the program. 
6. National Institute of Health Stroke Scale (NIH SS): is a tool used to objectively quantify 
the impairment caused by a stroke. It is composed of 11 items, each of which scores a 
specific ability between a 0 and 4. 
7. Visual analogue scale (VAS) for anxiety: This tool is a visual scale of 0-10 where the 
subject can rate their level of anxiety where 0 is no anxiety, and 10 is the worst anxiety that 
the subject has ever felt. 
8. Visual Analogue Scale (VAS) for pain /comfort: This tool is a visual scale of 0-10 where 
the subject can rate their level of pain where 0 is no pain, and 10 is the worst pain that the 
subject has ever felt. 
9. Side Effects / Adverse event tracking Questionnaire for rTMS: After each session, subjects 
will complete a questionnaire to evaluate potential common adverse effects rTMS 
(headache, neck pain, itching and redness at the site of stimulation) on a 5-point scale. 
10. The Antidepresant Side-Effect Checklist (ASEC): The ASEC is a questionnaire that 
assesses the possible appearance of side effects related to the use of common 
antidepresants, their severity and if they are linked or not to the drug (Uher, 2010).  
11. Blinding Questionnaire: to be performed at the end of the daily stimulation sessions and at 
the end of the weekly stimulation sessions.. This questionnaire will ask the rater and the 
subjects whether the intervention was sham or active rTMS . The confidence of these 
responses will be rated from 0 to 5 – 0 being no confidence and 5- total confidence. If the 
subject is interested in knowing what stimulation he/she received, the co-investigator may 
inform the subject when his/her participation in the trial has ended. . 


Detailed Protocol 16 
12. A log of the hours of therapy that patients are receiving and the meditations they are taking 
will be kept and updated every week.  
Assessment of cortical excitability and plasticity – single and paired pulse TMS and PAS: 
 
Aim 1: Determine whether low-frequency rTMS of the unaffected M1 associated with fluoxetine 
offers an additional benefit on motor function over pharmacotherapy. 
 
We will investigate changes in cortical excitability by evaluating the motor evoked potential 
(MEP) and the resting motor threshold (MT) (with the same methods as in our previous study 
(Fregni et al., 2006b)). We will also measure intracortical excitability using the technique of 
paired-pulse, and interhemispheric differences using transcallosal inhibition. Both the affected and 
unaffected M1 will be studied.  
 
We will investigate the resting motor threshold (measured following the technique described by 
(Rossini et al., 1994)) before and after stimulation. For the MEP study, we will initially adjust 
TMS intensity to achieve a baseline MEP in the first dorsal interosseous of about 1 mV peak-to-
peak amplitude before intervention. Stimulation intensity will be kept constant for each subject 
throughout the experiment. The MEPs will be recorded and stored in a PC computer for off-line 
analysis. We will record 10 MEPs for each time point (immediately before and after the rTMS 
stimulation) and average their peak-to-peak amplitude and area-under-the-curve. 
I. 
For the paired-pulse study, a subthreshold conditioning stimulus will be applied, 
followed at a variable interstimulus interval (ISI) by a second test (suprathreshold) 
stimulus. We will use the following ISIs: 2, 3, 6, 10, and 12.  The percentage of 
inhibition or facilitation for each ISI before and after stimulation will be calculated 
II. 
To measure changes in transcallosal inhibition, a suprathreshold stimulus will be 
applied to the motor cortex of one hemisphere, and ten milliseconds later a threshold 
stimulus will be applied to the contralateral motor cortex. The percentage of inhibition 
for each stimulus before and after stimulation will be calculated. 
III. 
PAS: To measure LTP-like in the motor cortex, we will use the measure of paired 
associative stimulation (PAS). For PAS, 160 pairs of peripheral nerve stimulation and 
TMS of motor cortex will be delivered at 0.1 Hz. Stimulation of the median nerve will 
precede TMS of M1 using an interstimulus interval (ISI) of 25 milliseconds (PAS-25). 
It has been shown that in PAS-25, the two inputs via peripheral nerve stimulation and 
via TMS reaches motor cortex simultaneously which results in facilitation of the MEP 
induced by TMS (Stefan, 2000). PAS-25 has been used as a robust marker to assess 
cortical plasticity in M1. 
Transcranial Magnetic Stimulation: TMS will be performed with a Bistim2 stimulator (Magstim 
Company LTDA, UK) and a commercially available 70 mm figure-of-eight coil. Responses to 
stimuli applied to the motor cortex will be recorded from the contralateral first dorsal interosseous 
(FDI) muscle. Silver/silver chloride electrodes will be placed over the muscle belly (active 
electrode) and joint or tendon of the muscle (reference electrode) to record MEPs. A ground 
electrode will be placed over the wrist. MEPs will be amplified and filtered using a Powerlab 4/30 
with a band pass of 20-2000 kHz. Signals will be fed to a personal computer for off-line analysis 
using data collection software and conditional averaging software. In the case we are not able to 


Detailed Protocol 17 
locate the motor threshold in the affected hemisphere; we will not perform MEP’s, Paired Pulse, 
and PAS in the affected hemisphere. 
 
VIII. 
BIOSTATISTICAL ANALYSIS 
 
Sample size justification: 
We planned a sample size based on our SELECT-tDCS trial combining non-invasive brain 
stimulation and sertraline for the treatment of depression and in addition the FLAME trial testing 
fluoxetine on motor function in stroke. Using these two studies, our calculation showed that a 
sample size of 30 participants would provide at least 80% power (alpha=0.05) to detect an effect 
size of 0.9 (considering the treatment difference between the two independent groups) in our main 
outcome between the active and sham rTMS group. Although this sample is small and may rely 
on large effects found in these two studies, this is a realistic sample for this initial phase II study 
as the effect size of 0.9 is smaller than the effect size of these two studies. Finally there will also 
be good statistical power to detect moderate effects of treatment on the secondary outcomes. 
[Given that our subaim 1 (added in the specific aims part) has the goal of assessing whether the 
effects found in the main comparison are also superior to spontaneous recovery, we added another 
group with the same size (15 subjects) as to provide the same power for the two group comparison 
in subaim 1 (real rTMS+fluoxetine vs. sham rTMS+placebo fluoxetine and sham rTMS+fluoxetine 
vs. sham rtMS+placebo fluoxetine)] 
 
All analyses will be conducted according to the principle of intention-to-treat (using regression-
based single imputation method). We will also perform an additional sensitivity analysis in which 
we will use the method of last observation carried forward.  
 
For the first aim, the primary outcome will be motor function changes as indexed by Jebsen 
Taylor Hand Function test and secondary outcome will be Fugl-Meyer motor scores. Differences 
between the two groups will be tested using Student's t-test and, in addition, we will adjust for 
important baseline variables and also test the time effect in general mixed longitudinal models. 
Secondary analyses will be conducted in an exploratory manner (no correction for multiple 
comparisons). [We will also conduct exploratory correlational analysis as to understand whether 
beneficial effects of the combined intervention (active rTMS and fluoxetine) are associated with 
any baseline characteristics as to explore potential predictors of the effects of treatment. This result 
may also be used along with results for aim 2 to understand the mechanisms of the combined 
treatment.] 
 
[For subaim 1: the primary outcome will be motor function changes as indexed by Jebsen Taylor 
Hand Function test and secondary outcome will be Fugl-Meyer motor scores. We will conduct the 
same analysis as aim 1 (Differences between the two groups will be tested using Student's t-test 
with adjustment for covariates) but in this case we conduct two comparisons (real 
rTMS+fluoxetine vs. sham rTMS+placebo fluoxetine and sham rTMS+fluoxetine vs. sham 
rtMS+placebo fluoxetine)] 
 
For the second aim, we will initially build a mixed ANOVA model in which the dependent 
variable will be the parameters of cortical excitability and plasticity (PAS) indexed by 


Detailed Protocol 18 
neuropsychological measures. The independent variables will be group [(active and placebo 
control)], time and the interaction group/time. [If we find a significant interaction effect between 
group and time, we will confirm our hypothesis that TMS induces a significant differential 
plasticity when compared to fluoxetine alone. Furthermore we will conduct additional analysis in 
which we will change the groups in the variable group (real rTMS+fluoxetine vs. sham 
rTMS+placebo fluoxetine and sham rTMS+fluoxetine vs. sham rtMS+placebo fluoxetine)  
 
 
Unexpected findings and discussion: In case we obtain unexpected results (i.e. we do not confirm 
our initial hypothesis that TMS plus fluoxetine has not a superior effect than the control placebo 
group in motor function as indexed by clinical and neurophysiological measures), this would still 
be interesting to report as we will explore possible mechanism of actions that lead to these 
unexpected results] 
• rTMS + fluoxetine vs. sham rTMS + fluoxetine and/or placebo control; clinical results 
positive and neurophysiological data positive: This is our expected hypothesis. 
• rTMS + fluoxetine vs. sham rTMS + fluoxetine; clinical results 
negative/neurophysiological results positive: TMS combined with fluoxetine induces 
differential plasticity however the impact in clinical outcomes is minor which provides 
good evidence that the combined treatment may not be useful. 
•  rTMS + fluoxetine vs. sham rTMS + fluoxetine;  
clinical results 
positive/neurophysiological results negative: This would be also an interesting result as 
the differential clinical improvements of the combined treatment are not mediated by 
motor cortex plasticity –we would then discuss potential mechanisms such as subcortical 
or cerebelar changes in the motor system. 
• rTMS + fluoxetine vs. sham rTMS + fluoxetine and/or placebo control; clinical results 
negative/neurophysiological results negative: In case we do not find differential effects in 
both outcomes, we will then use our third group to understand whether fluoxetine has a 
superior effect than placebo only as to understand whether there was a ceiling effect of 
the combined treatment or whether the population selected for this study was not 
responsive for this treatment 
 
 
IX. 
RISKS AND DISCOMFORTS 
 
Repetitive Transcranial Magnetic Stimulation:  
Repetitive transcranial magnetic stimulation may result in a small chance of inducing local pain, 
neck pain, transient headache, or toothache. In such prior cases, headaches induced by rTMS can 
be resolved with acetaminophen or aspirin, and typically disappear shortly after sitimulation.   
 
Repetitive TMS equipment produces a clicking sound when a current is passed through the 
stimulation coil. This click can result in ringing in the ear and temporary auditory threshold shifts 
if no protection is used. In order to prevent this potential adverse effect investigators and subjects 
will wear earplugs during TMS. Animal and human studies have demonstrated that ear plugs can 
effectively prevent the risk of hearing disturbance due to repetitive TMS.   
 


Detailed Protocol 19 
Repetitive TMS has rarely been associated with a possible risk of seizure induction, which has 
been rarely reported. In fact, according to the 2009 safety and ethical consensus guideline on 
repetitive TMS, the 10 year prevalence of seizure was described as “extremely rare” (Rossi et al, 
2009). The literature has even shown a protective effect against seizures in low frequency rTMS, 
while showing a “possible” 0.4% crude risk of high frequency rTMS, limited only to epileptic 
populations (Rossi et al, 2009). Of note, this, population is excluded from in this study. There are 
other extra-ordinarily rare reports, including electrode-induced skin injury, which can be 
minimized by attentive vigilance during the technique. rTMS has also been associated with a 
hypothetical risk of structural brain changes, histotoxicity, and transient TSH and lactate levels, 
all with inconsistent findings in the literature, of no determined implication to date (Rossi et al, 
2009). The current uses of rTMS have been determined to be overall very safe, especially when 
used under the safety guidelines of the recent 2008 Safety, ethical considerations, and application 
consensus guidelines, of which the principal investigator of this study was one of the authors 
(Rossi et al, 2009). 
 
Single-Pulse and Paired-Pulse Transcranial Magnetic Stimulation: 
We will be using a different kind of stimulation called Transcranial Magnetic Stimulation 
(TMS). TMS is different from rTMS, because TMS is a method of evaluating changes in the 
brain, whereas rTMS is a method of inducing changes in the brain. We will use TMS to measure 
whether rTMS caused any changes in cortical excitability and if there is any correlation between 
changes in cortical excitability with motor improvement. 
 
We will be using single and paired pulse TMS as a diagnostic tool. It does not change cortical 
excitability or brain activity. There is a small chance of single pulse TMS inducing a mild, transient 
headache or neck pain. In such prior cases, headaches induced by TMS can be resolved with 
acetaminophen or aspirin. 
 
TMS equipment produces a clicking sound when a current is passed through the stimulation coil. 
This click can result in ringing in the ear and temporary auditory threshold shifts if no protection 
is used. In order to prevent this potential adverse effect investigators and subjects will wear 
earplugs during TMS. Animal and human studies have demonstrated that ear plugs can effectively 
prevent the risk of hearing disturbance due to repetitive TMS.   
 
Fluoxetine: 
The dose to be used in this trial (20mg) is the standard dose that currently is being used as off label 
treatment in several rehabilitation centers to promote motor recovery after stroke. The safety 
profile of this dose has been also established in several studies in the psychiatric population where 
chronic usage is the common denominator and tolerance and safety has been demonstrated, the 
most common adverse effects are gastrointestinal issues that usually are transient and self-limited. 
In the FLAME trial the reported adverse effects observed in the active group were transient 
digestive disorders and insomnia, while the former was directly attributable to fluoxetine, the later 
was a combination of several factors involved in the care of acute patients. The most expected side 
effects are: dry mouth, drowsiness, insomnia, blurred vision, headache, constipation, diarrhea, 
increased or decreased appetite, nausea or vomiting, problems with urination, problems with the 
sexual function, palpitations, light-headedness, dizziness, sweating, hyperthermia, tremor, 
disorientation, yawning and weight gain. We will monitor the occurrence of adverse effects using 


Detailed Protocol 20 
the Antidepressant Side Effect Checklist (ASEC) . For inpatients, this document will be handled 
by the study personnel and the clinicians involved in the patient’s care and for outpatients by a co-
investigator.  Dr. Black-Shaffer will carefully review all adverse effects during the study for all 
the subjects. Dr. Black-Shaffer, the director of stroke service, also has experience in the use of 
fluoxetine for stroke rehabilitation as it is also used in one of her studies. 
 
Behavioral assessments/Questionnaires:  
There are no potential risks posed to participants with respect to behavioral tasks.  Though 
participants may become fatigued during testing, they will be informed that they are allowed to 
take a break at any point during the experiment and that they may end their participation at any 
time. 
 
 
X. 
POTENTIAL BENEFITS 
 
As the study we aim to conduct is focused on basic research, the subjects enrolled will derive no 
direct benefit. The results of this study may benefit subsequent future stroke patients with 
hemiparesis or hemiplegia, if rTMS combined with fluoxetine prove to improve motor function. 
  
We envision that in the near future, the information obtained from the proposed research project 
will provide a better understanding of motor function recovery after stroke.  
 
 
XI. 
MONITORING AND QUALITY ASSURANCE 
 
Data for this study will be collected from subjects in several forms: scores from a multitude of 
questionnaires measuring motor function, mood and quality of life, measures of cortical 
excitability, as well as demographic data. All data will be assigned a subject number, and the 
accompanying name will be deleted, so that it is de-identified. All data collected from subjects will 
be maintained in a secured and password protected database, of which only the IRB trained and 
approved study staff will have access, including the PI, Co-I’s, research assistant, and research 
fellow. In addition, data on paper (i.e. IRB approved questionnaires in subject folders) will be kept 
in a secured and locked storage room, of which only IRB approved study staff have access, within 
the Laboratory of Neuromodulation at Spaulding Rehabilitation Hospital. The research assistant 
also maintains a password protected database of subject contact information, for those subjects 
who express interest in our research by phone. 
 
Approval of protocol, informed consent procedures, and recruitment will be obtained from the IRB 
during annual reviews.  Adverse events, data and procedural reviews will be conducted by the 
study coordinator and Dr. Fregni on a monthly basis, in consultation with study staff, to identify 
and ameliorate any potential safety issues. Any safety concerns about the protocol will be brought 
to the immediate attention of Dr. Fregni. Safety will be monitored by the Adverse Effects 
Questionnaire, anti-depressant side effects checklist, and rTMS/TMS side effects questionnaire. 
The Principal Investigator will be responsible for data monitoring, accuracy and completeness of 
data collection, and data storage. Data will be reviewed at completion of each subject’s 
participation in the study.  


Detailed Protocol 21 
 
As the sample size is relatively small, we do not plan on performing interim data analysis.  Adverse 
events, data, and procedures will be reviewed by Dr. Fregni and his team.  All expected and 
unexpected adverse outcomes will be reported to the IRB according to the Adverse Event 
Reporting guidelines. 
 
A trained co-investigator on the study will administer the rTMS, sensory exams and the other 
evaluations. Prior to performing any study procedures, the study staff member was trained in the 
techniques of rTMS as well as all aspects of the evaluations. This study staff member was then 
evaluated by the PI of the study. The PI has given confirmation that the co-investigator is qualified 
to administer the stimulation and the evaluations. 
 
All procedures in the Neuromodulation Center will be performed by research personnel having 
Basic Life Support (BLS) certification.  All staff performing study procedures must have reviewed 
and understand hospital and building 79-96 emergency procedures. 
 
Additionally,  a one-sheet medical information summary, highlighting important medical issues 
(pertinent PMH, medications, allergies, functional limitation/neurologic deficits, emergency 
contact, PCP) will be available for each patient participating as the initial page of their study 
binder. Therefore, in case of emergency, the clinician will have this information easily accessible. 
 
Emergency Procedure Plan 
 
Testing of research subjects in experiments from the Neuromodulation Center will be conducted 
in two sites (79-96 Neuromodulation Center and SRH). Subjects will be preferentially tested at 
SRH when equipment for testing and stimulation allows.  Stimulation sessions will take place in 
79/96 if there is an equipment restriction or scheduling conflict that would affect the scientific 
validity of the protocol (ie, would cause a missed visit during the 2 weeks of daily stimulation 
visits). All assessment based visits will be conducted in 79/96 (under the coverage plan explained 
below) as these tests require sensitive equipment which cannot be moved between 79/96-SRH 
after having already been calibrated and tested here.  
 
79-96 Neuromodulation testing 
 
Testing in the 79-96 building will take place with in-house licensed clinicians available (physician 
or RN). To ensure that coverage is available, one of the coordinators of the Neuromodulation lab 
will send out weekly e-mails to in-house clinicians to confirm their schedules for the following 
week.  Additionally, daily e-mails will be sent to all laboratory members with the medical coverage 
schedule for the day. The clinicians will be copied on these daily e-mails, and thus can let the 
Neuromodulation lab know if something has changed in their schedule. Finally, these weekly 
schedules will be posted on a white board in the main reception area of the lab so that all staff may 
readily see who is available when.  
 
Should an emergency arise during stimulation that requires immediate medical attention, the 
investigator will use the established emergency procedures for 79/96. This includes alerting the 
in-house clinician, dialing the emergency number (9-911) and reporting the nature and location of 


Detailed Protocol 22 
the medical emergency. Staff will assist the clinician as directed until EMS arrives. After using 
this system, the investigator will follow the Laboratory and IRB policies for adverse event 
reporting, including notification of the Principal Investigator and the Medical Monitor and filing 
of an adverse event report.  Should any minor incidents occur during stimulation that do not require 
immediate medical attention, the PI or licensed physician will be contacted to assess these issues 
and initiate appropriate action.  
 
SRH testing – Research Floor 
Whenever is possible, testing in SRH will be prioritized especially for patients participating in the 
stimulation sessions, when equipment permits. Coverage for emergencies during hospital testing 
(SRH) is the emergency response team.  The team is activated by dialing 8-6666, giving location 
and type of emergency. 
 
If due to equipment restrictions (ie, sensitive equipment that cannot be moved between 79-96 and 
SRH) or scheduling conflicts prevents subjects from being able to be stimulated in SRH, subjects 
may receive stimulation in 79-96 in accordance with the plan listed above in order to maintain the 
scientific validity of the protocol. 
 
 In addition to this support, the Principal Investigator or a licensed physician familiar with the 
research study will be available either on-site or available by pager, for all stimulation sessions. If 
this PI is unavailable, this licensed physician will be available to assist with identification and 
notification of emergencies.  
 
In order to further monitor and quality assurance we developed a plan for assessment via an 
independent medical monitor. The following plan has been proposed to NIH for the independent 
medical monitor: 
 
The independent medical monitor will be responsible to assess adverse events and reasons for 
dropouts.  
• Adverse events will be collected from the start of neural stimulation and through the end 
of study participation.  All adverse events regardless of attribution to active neural 
stimulation will be collected and recorded, using standard adverse event forms for brain 
stimulation currently used at Harvard Medical School site.  These forms will be included 
as part of the IRB review package. 
• A diagnosis rather than signs, symptoms, and/or other clinical information will be recorded 
when possible.  Participants will be asked in an open-ended way about the presence of any 
adverse events; but also will be collected using the adverse effects questionnaire.  In this 
questionnaire, at each session, subjects will complete a questionnaire to evaluate potential 
adverse effects of stimulation (headache, neck pain, mood alterations, and seizures) on a 
5-point scale. The scale will also be administered at the follow-up.  Intensity will be graded 
as mild, moderate, or severe for each adverse event.  The likelihood that the event is related 
or not related to treatment will be noted. 
• Adverse Events (AEs) will be measured in several areas: seriousness, severity, length of 
duration, and if any causal relationship exists with the intervention. 


Detailed Protocol 23 
• Serious AEs (SAEs) will be defined as adverse events that resulted in death, were life-
threatening/disabling, and/or required hospitalization. Please see the human subjects 
section for further details.  
• According to Partners/Harvard Medical School policy, where the human trials will be 
conducted (and Highland Instruments will be bound by their IRB as part of an institutional 
agreement and FWA00018902) the reporting for any unanticipated untoward or 
unfavorable medical occurrence, including abnormal sign (for example, abnormal physical 
exam or laboratory finding), symptom, or disease, that indicates that the research places 
subjects are at increased risk of physical or psychological harm than previously known or 
recognized are to be submitted through as an Adverse Event will include: 
o a detailed description of the adverse event;  
o the basis for determining that the event is unexpected in nature, severity, or 
frequency;  
o the basis for determining that the event is related or possibly related to the research 
procedures;  
o the basis for determining that the research places subjects at an increased risk of 
harm (i.e., a serious adverse event); and  
o whether any changes to the research or other corrective actions are warranted. 
• Events will be medically evaluated as appropriate, including testing and referral.  All 
applicable local regulatory requirements related to the reporting of serious adverse events 
to regulatory authorities and the IRB will be followed during this study.  Serious adverse 
events will be promptly reported to NIH and IRB.   
o The issue of placing the study on hold will be raised by the investigators with our 
local IRB if any serious adverse events occur. 
• Data from this adverse effect questionnaire will be imputed into a secure database for 
medical monitor review. Data input will be performed by a blinded co-investigator and the 
medical monitor will have also independent access to database and all study materials.  
• The independent medical monitor will review data on retention and follow-up including 
reasons for patient dropout (Monitoring missing data). The reasons for dropout will be 
detailed in the report document that will be reviewed by the medical monitor. 
• The independent medical monitor will review data on adverse events and safety (according 
to the guidelines described in this plan) and will report any concerns or issues with the 
NINDS and the PI, and recommending to the NINDS and PI the continuation, modification, 
or conclusion of the trial, while protecting the confidentiality of the trial data and the results 
of monitoring.  
o The independent medical monitor will review the data at least after every 6 patients 
or whether there is any serious adverse event reported as defined above.  
• In order to ensure the likelihood of successful and timely trial completion, the medical 
monitor will also assess: 
o participant recruitment  
o protocol adherence 
o data quality and completeness 
o data confidentiality 
o Recommend planned adaptations based on pre-specified plans and decision rules.  
 
 


Detailed Protocol 24 
XII. 
REFERENCES 
 
Adeyemo, B. O., Simis, M., Macea, D., & Fregni, F. Systematic Review of Parameters of 
Stimulation: Clinical Trial Design Characteristics and Motor Outcomes in Noninvasive Brain 
Stimulation in Stroke. Frontiers in Psychiatry, 3, 8. 
 
Acler M, Robol E, Fiaschi A, Manganotti P. A double blind placebo controlled RCT to 
investigate the effects of serotonergic modulation on brain excitability and motor recovery in 
stroke patients. J Neurol 2009; 256: 1152-1158. 
 
Brown, J. A., Lutsep, H., Cramer, S. C. & Weinand, M. (2003) Motor cortex       stimulation for 
enhancement of recovery after stroke: case report. Neurol Res, 25, 815-8. 
 
Brown, J. A., Lutsep, H. L., Weinand, M. & Cramer, S. C. (2006) Motor cortex stimulation for 
the enhancement of recovery from stroke: a prospective, multicenter safety study. Neurosurgery, 
58, 464-73. 
 
Brunoni, A. R., Valiengo, L., Baccaro, A., Zanao, T. A., de Oliveira, J. F., Goulart, A., et al. 
(2013). The Sertraline vs Electrical Current Therapy for Treating Depression Clinical Study: 
Results From a Factorial, Randomized, Controlled Trial. JAMA Psychiatry, 6, 1-9.  
 
Chollet, F, Tardy J, Albucher J-F, Thalamas C, et al.  Fluoxetine for motor recovery after acute 
ischaemic stroke (FLAME):  a randomized placebo-controlled trial. Lancet Neurol 2011; 10: 
123-130.  
 
Dam M, Tonin P, DeBoni A, Pizzolato G, Casson S, Ermaniu M. Effects of fluoxetine and 
maprotiline on functional recovery in poststroke hemiplegic patients undergoing rehabilitation 
therapy. Stroke  1996; 27: 1211-1214. 
 
Fregni, F., Santos, C. M., Myczkowski, M. L., Rigolino, R., Gallucci-Neto, J., Barbosa, E. R., 
Valente, K. D., Pascual-Leone, A. & Marcolin, M. A. (2004) Repetitive transcranial magnetic 
stimulation is as effective as fluoxetine in the treatment of depression in patients with 
Parkinson's disease. J Neurol Neurosurg Psychiatry, 75, 1171-4. 
 
Fregni, F., Boggio, P. S., Lima, M. C., Ferreira, M. J., Wagner, T., Rigonatti, S. P., Castro, A. 
W., Souza, D. R., Riberto, M., Freedman, S. D., Nitsche, M. A. & Pascual-Leone, A. (2006a) A 
sham-controlled, phase II trial of transcranial direct current stimulation for the treatment of 
central pain in traumatic spinal cord injury. Pain, 122, 197-209. 
 
Fregni, F., Boggio, P. S., Valle, A. C., Rocha, R. R., Duarte, J., Ferreira, M. J., Wagner, T., 
Fecteau, S., Rigonatti, S. P., Riberto, M., Freedman, S. D. & Pascual-Leone, A. (2006c) A sham-
controlled trial of a 5-day course of repetitive transcranial magnetic stimulation of the unaffected 
hemisphere in stroke patients. Stroke, 37, 2115-22. 
 
Fregni, F., Boggio, P. S., Mansur, C. G., Wagner, T., Ferreira, M. J., Lima, M. C., Rigonatti, S. 
P., Marcolin, M. A., Freedman, S. D., Nitsche, M. A. & Pascual-Leone, A. (2005a) Transcranial 


Detailed Protocol 25 
direct current stimulation of the unaffected hemisphere in stroke patients. Neuroreport, 16, 1551-
1555. 
 
Gangitano, M., Valero-Cabre, A., Tormos, J. M., Mottaghy, F. M., Romero, J. R. & Pascual-
Leone, A. (2002) Modulation of input-output curves by low and high frequency repetitive 
transcranial magnetic stimulation of the motor cortex. Clin Neurophysiol, 113, 1249-57.  
 
Gianotti G, Antonucci G, Marra C, Paolucci S. Relation between depression after stroke 
antidepressant therapy, and functional recovery. J Neurol Neurosurg Pscychiatry 2001; 71: 208-
261 
 
Hoffman, R. E. & Cavus, I. (2002) Slow transcranial magnetic stimulation, long-term 
depotentiation, and brain hyperexcitability disorders. Am J Psychiatry, 159, 1093-102. 
 
Huang, Y. Z., Edwards, M. J., Rounis, E., Bhatia, K. P. & Rothwell, J. C. (2005) Theta burst 
stimulation of the human motor cortex. Neuron, 45, 201-6. 
 
Hummel, F., Celnik, P., Giraux, P., Floel, A., Wu, W. H., Gerloff, C. & Cohen, L. G. (2005) 
Effects of non-invasive cortical stimulation on skilled motor function in chronic stroke. Brain, 
128, 490-9. 
 
Hummel, F. & Cohen, L. G. (2005) Improvement of motor function with noninvasive cortical 
stimulation in a patient with chronic stroke. Neurorehabil Neural Repair, 19, 14-9. 
 
Jebsen, R. H., Taylor, N., Trieschmann, R. B., Trotter, M. J. & Howard, L. A. (1969) An 
objective and standardized test of hand function. Arch Phys Med Rehabil, 50, 311-9. 
 
Jorge RE, Acion L, Moser D, Adams HP, Robinson RG. Escitalopram and enhancement of 
cognitive recovery following stroke. Arch Gen Psychiatry 2010; 67(2): 187-196. 
 
Khedr, E. M., Ahmed, M. A., Fathy, N. & Rothwell, J. C. (2005) Therapeutic trial of repetitive 
transcranial magnetic stimulation after acute ischemic stroke. Neurology, 65, 466-8. 
 
Lloyd-Jones D, Adams R, Carnethon M, De Simone G, Ferguson Tb, Flegal K, Ford E, Furie K, 
Go A, Greenlund K, Haase N, Hailpern S, Ho M, Howard V, Kissela B, Kittner S, Lackland D, 
Lisabeth L, Marelli A, Mcdermott M, Meigs J, Mozaffarian D, Nichol G, O’donnell C, Rogerr 
V, Rosamon W, Sacco R, Sorlie P, Stafford R, Steinberger J, Thom T, Wasserthiell-Smoller S, 
Wong N, Wylie-Rosett J, Hong Y; American Heart Association Statistics Committee and Stroke 
Statistics Subcommittee. Heart disease and stroke statistics--2009 update: a report from the 
American Heart Association Statistics Committee and Stroke Statistics Subcommittee. 
Circulation. 2009 Jan 27;119(3):480-6. Erratum in: Circulation. 
 
Maeda, F., Keenan, J. P., Tormos, J. M., Topka, H. & Pascual-Leone, A. (2000) Modulation of 
corticospinal excitability by repetitive transcranial magnetic stimulation. Clin Neurophysiol, 111, 
800-5. 
 


Detailed Protocol 26 
Mansur, C. G., Fregni, F., Boggio, P. S., Riberto, M., Gallucci-Neto, J., Santos, C. M., Wagner, 
T., Rigonatti, S. P., Marcolin, M. A. & Pascual-Leone, A. (2005) A sham stimulation-controlled 
trial of rTMS of the unaffected hemisphere in stroke patients. Neurology, 64, 1802-4. 
 
Marconi B, Filippi Gm, Koch G, Giacobbe V, Pecchioli C, Versace V, Camerota F, Saraceni 
Vm, Caltagrione C. Long-term effects on cortical excitability and motor  recovery induced by 
repeated muscle vibration in chronic stroke patients. Neurorehabil Neural Repair. 2011 
Jan;25(1):48-60. 
 
Narushima K, Paradiso S, Moser DJ, Jorge R, Robinson RG. Effect of antidepressant therapy on 
executive function after stroke. Br J Psychiatry 2007 Mar; 190: 260-265. 
 
Nitsche, M. A. & Paulus, W. (2001) Sustained excitability elevations induced by transcranial DC 
motor cortex stimulation in humans. Neurology, 57, 1899-901. 
 
Nowak Da, Grefkes C, Ameli M, Fink Gr. Interhemispheric competition after stroke: brain 
stimulation to enhance recovery of function of the affected hand. Neurorehabil Neural Repair. 
2009 Sep;23(7):641-56. 
 
Pariente J, Loubinoux I, Carel C, Albucher J-F, Leger A, et al. Fluoxetine modulates motor 
performance and cerebral activation of patients recovering from stroke. Ann Neurol 2001; 50: 
718-729. 
 
Pascual-Leone, A., Walsh, V. & Rothwell, J. (2000) Transcranial magnetic stimulation in 
cognitive neuroscience--virtual lesion, chronometry, and functional connectivity. Curr Opin 
Neurobiol, 10, 232-7. 
 
Plautz, E. J., Barbay, S., Frost, S. B., Friel, K. M., Dancause, N., Zoubina, E. V., Stowe, A. M., 
Quaney, B. M. & Nudo, R. J. (2003) Post-infarct cortical plasticity and behavioral recovery 
using concurrent cortical stimulation and rehabilitative training: a feasibility study in primates. 
Neurol Res, 25, 801-10.  
 
Rogers LM, Brown DA, Stinear JW. The effects of paired associative stimulation on knee 
extensor motor excitability of individuals post-stroke: A pilot study. Clin Neurophysiol. 2010 
Dec 1. 
 
Rossi S, Hallett M, Rossini PM, Pascual-Leone A; Safety of TMS Consensus Group (2009) 
Safety, ethical considerations, and application guidelines for the use of transcranial magnetic 
stimulation in clinical practice and research. Clin Neurophysiol, 120, 2008-39. 
 
Rossini, P. M., Barker, A. T. & Berardelli, A. (1994) Non-invasive electrical and magnetic 
stimulation of the brain spinal cord and roots: basic princeples and procedures for routine clinical 
application: report of an ICFN committee. Electroencephalogr Clin Neurophysiol, 91, 79-91. 
 
Triggs, W. J., Mccoy, K. J., Greer, R., Rossi, F., Bowers, D., Kortenkamp, S., Nadeau, S. E., 
Heilman, K. M. & Goodman, W. K. (1999) Effects of left frontal transcranial magnetic 


Detailed Protocol 27 
stimulation on depressed mood, cognition, and corticomotor threshold. Biol Psychiatry, 45, 
1440-6. 
Uher, R., Farmer, A., Henigsberg, N., Rietschel, M., Mors, O., Maier, W., ... & Aitchison, K. J. 
(2009). Adverse reactions to antidepressants. The British Journal of Psychiatry, 195(3), 202-210. 
 
Wang, H., Wang, X., Wetzel, W. & Scheich, H. (1999) Rapid-rate transcranial magnetic 
stimulation in auditory cortex induces LTP and LTD and impairs discrimination learning of 
frequency-modulated tones. Electroencephalogr Clin Neurophysiol Suppl, 51, 361-7. 
 
Ward Ns, Brown Mm, Thompson Aj, Frackowiak RS. Neural correlates of motor recovery after 
stroke: a longitudinal fMRI study. Brain 2003; 126: 2476–96. 
Zittel S, Weiller C, Liepert J. Citalopram improves dexterity in chronic stroke patients. 
Neurorehabilitation and Neural Repair 2008; 22(3) 311-314