Efficacy of intermittent Theta Burst Stimulation (iTBS) and 10-Hz high-frequency repetitive transcranial magnetic stimulation (rTMS) in treatment-resistant unipolar depression: study protocol for a randomised controlled trial
Bulteau et al. Trials
Efficacy of intermittent Theta Burst Stimulation (iTBS) and 10-Hz high- frequency repetitive transcranial magnetic stimulation (rTMS) in treatment-resistant unipolar depression: study protocol for a randomised controlled trial
Samuel Bulteau 0 1
Veronique Sébille 0
Annabelle Bonnin-Rivalland 1
Edouard Laforgue 1
Anne Pichot 1
Pierre Valrivière 1
Jean-Marie Vanelle 1
Anne Sauvaget 0 1
0 University of Nantes, University of Tours, INSERM, SPHERE U1246 , F-44000 Nantes , France
1 CHU de Nantes, Clinical Investigation Unit 18, Department of Addictology and Consultation-liaison Psychiatry , F-44000 Nantes , France
Background: The treatment of depression remains a challenge since at least 40% of patients do not respond to initial antidepressant therapy and 20% present chronic symptoms (more than 2 years despite standard treatment administered correctly). Repetitive transcranial magnetic stimulation (rTMS) is an effective adjuvant therapy but still not ideal. Intermittent Theta Burst Stimulation (iTBS), which has only been used recently in clinical practice, could have a faster and more intense effect compared to conventional protocols, including 10-Hz high-frequency rTMS (HF-rTMS). However, no controlled study has so far highlighted the superiority of iTBS in resistant unipolar depression. Methods/design: This paper focuses on the design of a randomised, controlled, double-blind, single-centre study with two parallel arms, carried out in France, in an attempt to assess the efficacy of an iTBS protocol versus a standard HF- rTMS protocol. Sixty patients aged between 18 and 75 years of age will be enrolled. They must be diagnosed with major depressive disorder persisting despite treatment with two antidepressants at an effective dose over a period of 6 weeks during the current episode. The study will consist of two phases: a treatment phase comprising 20 sessions of rTMS to the left dorsolateral prefrontal cortex, localised via a neuronavigation system and a 6-month longitudinal follow-up. The primary endpoint will be the number of responders per group, defined by a decrease of at least 50% in the initial score on the Montgomery and Asberg Rating Scale (MADRS) at the end of rTMS sessions. The secondary endpoints will be: response rate 1 month after rTMS sessions; number of remissions defined by a MADRS score of <8 at the endpoint and 1 month after; the number of responses and remissions maintained over the next 6 months; quality of life; and the presence of predictive markers of the therapeutic response: clinical (dimensional scales), neuropsychological (evaluation of cognitive functions), motor (objective motor testing) and neurophysiological (cortical excitability measurements). (Continued on next page) © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
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Discussion: The purpose of our study is to check the assumption of iTBS superiority in the management of unipolar
depression and we will discuss its effect over time. In case of a significant increase in the number of therapeutic
responses with a prolonged effect, the iTBS protocol could be considered a first-line protocol in resistant unipolar
Trial registration: ClinicalTrials.gov, Identifier NCT02376491. Registered on 17 February 2015 at http://clinicaltrials.gov.
Depression is a real public health problem. In 2020,
according to the World Health Organisation (WHO),
depression will be the second major cause of handicap and
premature death in the world after coronary diseases.
Standard treatment comprises support therapy
combined with medication. However, at least 40% of patients
do not respond to the initial treatment and 20% present
with persistent resistance to conventional
pharmacological treatments . It is, therefore, essential to find
efficient treatment alternatives for resistant depression.
The reference treatment in this case is still
electroconvulsive therapy (ECT) with a 48% response rate in the
event of severe resistance to pharmacological therapies
. Repetitive transcranial magnetic stimulation (rTMS)
is a non-invasive, focal, cortical stimulation technique
involving modulation of cortical excitability. It is an
upstream alternative to ECT and could close to match
comparable efficacy in the absence of psychotic
symptoms with a satisfactory duration and number of stimuli
[3, 4]. Its interest in the treatment of resistant unipolar
depression has clearly been established in conjunction
with antidepressant chemotherapy.
The efficacy of rTMS depends on its parameters
(stimulation site, orientation of the magnetic field,
number of stimuli delivered as well as the frequency,
intensity and duration of stimulation) . The two types of
dorsolateral prefrontal cortex (DLPFC) stimulation used
in the treatment of depression – high frequency to the
left (L-HF) and low frequency to the right (R-LF) – have
proved to be equi-effective [6–9]. Response rates on
average vary from 30 to 40% depending on the series
[10, 11], with a 58% response rate maintained at
3 months, then 33% at 6 months [12, 13].
Although these various parameters currently have yet
to be optimised, a new rTMS technique known as Theta
Burst Stimulation (TBS) has recently emerged. This
displays faster, more robust action compared to
conventional protocols , with excellent tolerability ,
provided that safety recommendations are followed .
Two different methods have been described: intermittent
(iTBS) and continuous Theta Burst Stimulation (cTBS)
with facilitating and inhibitory effects, respectively. iTBS
involves the application of bursts of three pulses at a
frequency of 50 Hz every 200 ms; therefore, at 5 Hz,
delivery is over 2 s and repeated every 10 s, 20 times in
succession. An uncontrolled study on a small sample
generated 70% of responses and 42% of remissions in
resistant unipolar depression following a course of iTBS
. These shorter sessions would be an additional
source of comfort for the patient not to mention the
lower cost of the session. It should be noted that a very
recent study highlighted the superiority of iTBS over
cTBS and placebo in the management of resistant
depression . In 2014, Bakker et al. demonstrated
similar efficacy with iTBS prefrontal dorsomedial bilateral
stimulation (6 min) and a 10-Hz protocol (30 min) in an
uncontrolled retrospective study . With regard to
recent scientific literature, various points must be
specifically investigated: controlled comparison of protocols
with the enrolment of a homogeneous population in
terms of treatment and clinical form of the condition
(most studies combine both bipolar and unipolar
disorder); duration of the effect with longitudinal
followup; and predictive response factors . The main
predictive therapeutic response factors identified to date
are age, duration of the episode, degree of therapeutic
resistance, clinical profile and, in particular, cognitive
impairment and psychomotor retardation [21, 22]. A
study of cortical excitability, which reflects the gabaergic
and glutamatergic transmission of cortical interneurones
(IN), could also prove promising in distinguishing
neurostimulation responder profiles. No controlled study
comparing the efficacy of iTBS versus conventional
rTMS protocols in unipolar resistant depression has
been published to date.
The aim of this randomised controlled trial is to
investigate the efficacy of iTBS versus 10-Hz high-frequency
transcranial magnetic stimulation (HF-rTMS) in a
population of patients suffering from unipolar depression
(Montgomery and Asberg Rating Scale (MADRS) score
of >20) despite the use of two antidepressant agents
during the current episode. Moreover, this trial will evaluate
whether certain specific clinical or neuropsychological
dimensions, objective measurements of psychomotor
retardation or even distinct cortical excitability profiles could
predict the efficacy of iTBS and HF-rTMS, respectively.
Study design, setting and recruitment
This is a randomised, controlled, double-blind,
singlecentre study. It is carried out at the Centre Hospitalier
Universitaire (University Hospital Centre) of Nantes,
France. The patients are randomly assigned to the iTBS
or the HF-rTMS group as shown in Fig. 1 (Flow Chart).
More specifically, the two parallel arms compare an
iTBS protocol to a so-called conventional protocol at
10 Hz . The stimulation target is identical in the left
dorsolateral prefrontal cortex (Brodmann areas 9 and
46), localised via Nextim® (software Eximia®)
neuronavigation. Participants are randomised to one of the
treatment groups using a computer programme included in
the electronic Case Report Form (e-CRF). This study has
been approved by the local Nantes Ouest IV Ethics
Committee (reference: ID RCB N°2014-AO1918-39) and
compiled in accordance with the principles of the
Declaration of Helsinki (final version 2004) as well as French
legislation (article L1121-160 and L1126-7 of the Public
Health Code). Additional quality standards are detailed
in Additional file 1 according to SPIRIT Check-list
requirements. All of the patients are given written and
verbal information about the study aim and procedures.
They sign a written Consent Form in order to take part in
the study. The aim is to enrol 60 patients who have been
put forward either by private or hospital psychiatrists in
the region, previously informed in writing of the study.
The 60 patients between 18 and 75 years old must
present with a current depressive episode considered
major (defined by Diagnostic and Statistical Manual of
Mental Disorders, fifth edition (DSM-V) diagnostic
criteria  and a MADRS score of >20 ) and resistant
(failure to respond to two sequences of different
antidepressants at an effective dose level over a period of 6 weeks
during the current episode). The current antidepressant is
continued at a stable dose throughout the study.
Each subject must be able to: understand the
information; take a decision; volunteer to participate; complete
the required questionnaires; take orally administered
treatment independently or have the necessary
assistance to do so throughout the study; and return to the
research centre for successive visits.
Patients presenting with at least one of the following
criteria are not be enrolled in the study: diagnosis of a
bipolar disorder; schizophrenia; addiction;
neurodegenerative disease; use of benzodiazepines (unless
prescribed over 3 months earlier at a stable dosage); use
of mood-modifying treatments (thyroid extracts,
interferon, corticosteroids); previous failure of ECT therapy;
anticonvulsant treatment; contraindication to magnetic
resonance imaging (MRI); contraindication to the
practice of rTMS: history of convulsions, progressive
neurological and neurosurgical disorders; any prosthetic
material or foreign body in situ (pacemaker, implantable
defibrillator); minors or persons deprived of liberty
Fig. 1 Flow Chart
following a legal or administrative decision or hospitalised
without consent, in guardianship; or pregnant women or
women of child-bearing age who are not using
contraception because of no available data about iTBS and
pregnancy (these women could receive, if absolutely necessary,
from case to case, conventional rTMS treatment, outside
the study). The same applies for subjects unable to
guarantee longitudinal follow-up.
In case of a serious adverse event or exacerbated
symptoms of depression, blind status will be lifted and
patients will receive appropriate care and retained in the
The screening visit V1 (D − 21 to D42) includes the
Patient Information Leaflet, collection of the Consent
Form and checking of inclusion/exclusion criteria. The
medical research team will be in charge of enrolment
and assignation of participants to the intervention. The
study manager and psychiatrist investigators can
generate the allocation sequence. Treatment is adjusted in line
with the course of therapy. A clinical examination is also
carried out and MRI prescribed to rule out any
neurological disorder and mark the neuronavigation target
during the baseline visit. The procedure is conducted
using a Siemens 1.5 T machine with the following
sequences: diffusion, T1 3D, FLAIR 2D and T2 rapid
During the baseline inclusion visit, the
inclusion/exclusion criteria are checked and participants randomised
into two groups by a computerised random number
generator with a permuted block design (ratio 1:1)
without stratification or minimisation. Block size and type of
variation (fixed or randomly) are not yet known by the
investigators to maintain adequate blinding.
Randomisation occurs in a recorded delay of maximum 72 h before
first rTMS session.
Research nurses, who perform rTMS sessions, are the
only persons to know the allocated sequence. Just after
the randomisation, they will receive an automatic e-mail
on their individual professional mail box. The session
will take place in a dedicated room with appropriate
noise control and a signal on the door during the session
to prevent accidental entry of investigators. Patients are
not told the group they belong to, will not have precise
description of rTMS parameters and duration and will
not be able to speak to each other. Both treatments will
be equally presented as efficient and superior to placebo.
Investigators will meet participants 1, 3 and 6 months
after the last rTMS session.
A patient who fails to respond to therapy (no decrease
of over 50% in the MADRS score) despite 4 weeks of
treatment will continue longitudinal follow-up in order
to avoid selection bias. A telephone call is made in the
second, fourth and fifth month outside the follow-up
consultations to keep in contact with patients and
remind them of the next appointment in order to avoid
their being lost to follow-up.
The study will last 33 months in total with 24 months
being the enrolment period. Patients are followed up
over a period of approximately 34 weeks in total
The following variables are documented during the
baseline visit: sociodemographic (age, gender, laterality,
professional and marital status); medical history (length of
illness, duration of current episode; psychiatric and
addictive comorbidities; somatic history; treatments
prescribed; degree of prior therapeutic resistance according
to the Maudsley Staging Model (MSM) ; basal
personality according to Cloninger’s Temperament and
Character Inventory (TCI) ).
The following variables are evaluated at the beginning
and end of treatment, as shown in Table 1: intensity of
the depression according to the MADRS ; the Beck
Depression Inventory 13 items (BDI 13)  and
Clinical Global Impression – Severity (CGI-S) ; and
quality of life with the Short-Form 36 Health Survey
(SF-36) . Response will be defined by a 50%
reduction of MADRS or BDI score, and remission by a
MADRS score of <8 and a BDI score of <10.
Potential explanatory variables to predict treatment
response in addition to sociodemographic and anamnestic
data are: clinical dimensions according to the Echelle de
Ralentissement Dépressif (ERD) (Depression Retardation
Scale) , the lack of pleasure Snaith-Hamilton
Pleasure Scale (SHAPS)  and Starkstein’s Apathy Scale
(SAS) ; cognitive functions according to the
Montreal Cognitive Assessment (MoCA) , the Verbal
Fluency Test  , the Modified Card Sorting Test
(MCST) , the digit span, the Wechsler Adult
Intelligence Scale (WAIS IV)  and the Trail Making
Test ; psychomotor retardation using specific tests
such as the Finger Taping Test (FTT) [40, 41], the
prehensile motor strength test , a test to measure
information processing speed (currently being validated by
our team ); and neurophysiological measurements of
cortical excitability, namely the cortical motor threshold,
short intracortical inhibition (SICI) and intracortical
facilitation (ICF) expressed as a percentage compared to
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the base value, and similarly for the cortical silent period
(CSP), which is carried out in both hemispheres [44–46].
All these scales are validated scales. Concerning the
motor retardation assessment, we recently showed that
administering a battery of psychomotor tests during
rTMS sessions is feasible, free of adverse effects and
well-tolerated by that population . Cortical
excitability is used in daily practice for patients with
neurodegenerative troubles with an excellent tolerance and
feasibility. Those measures are not performed the same
day (interval maximum 72 h) to avoid participant
overstimulation. An incentive of €80 is planned for cortical
excitability ancillatory measures.
The following scales are evaluated on a weekly basis:
the MADRS, the BDI and the CGI to investigate the
response kinetics and 1 month, 3 months and 6 months
after the endpoint as well as quality of life (SF-36). Data
collected directly from participants themselves will be
the BDI, the SAS, the SHAPS, the TCI and the SF-36.
Adherence to study quality standards is carried out by
an independent research associate. All significant
adverse events will be reported in the e-CRF by the
For the rTMS, an eight-shaped coil (Cool B65) and a
Magpro Stimulator X100 (Dantec Company,
Copenhagen, Denmark) are used. The resting motor
threshold (RMT) is recorded daily by a Natus Keypoint®
(Natus, Middleton, WI, USA). This is defined as the
intensity required to elicit at least five motor-evoked
potentials (MEPs) with a 50-μV peak-to-peak amplitude
out of ten consecutive stimulations when the coil is
placed over the left primary cortex (site for maximal
stimulation of the abductor pollicis brevis muscle). The
parameters used for HF-rTMS delivery are: 110% of
RMT; 10 Hz; 20 min; 4 s per train; 28 s intertrain
interval; 1600 pulses per day (40 trains of 40 pulses each).
The iTBS protocol will be: 80% of RMT; 50 Hz; 6 min;
600 pulses a day.
The target is left DLPFC corresponding to the junction
between Brodmann areas 9 and 46 according to an
individual’s 3D-MRI. During rTMS sessions, participants are
instructed to keep their eyes open and to be relaxed. All
subjects are evaluated before, once a week during the
rTMS course, at the endpoint and then at 1, 3 and
Primary outcome measures
The primary endpoint in our study will be the number
of responders per group, defined by a decrease of at least
50% in the initial MADRS score at the end of rTMS
Secondary outcome measures
The secondary endpoints will be: therapeutic response
rate corresponding to a MADRS score improvement of
>50% in each group 1 month after rTMS sessions;
number of remissions defined by a MADRS score of <8
at the endpoint and 1 month after; number of
therapeutic responses and remissions maintained in the
6 months following rTMS treatment; changes in quality
of life; and clinical, motor, neuropsychological and
neurophysiological (cortical excitability) therapeutic
A descriptive analysis of the data collected during each
patient evaluation will be carried out up until the final
evaluation. Specific time points for analysis are: end of
rTMS sessions and, 1, 3 and 6 months after the
treatment course. Continuous variables will be described
using median and range; and qualitative variables using
frequencies and percentages.
The final analysis will be conducted according to the
intent-to-treat (ITT) principle. The starting hypothesis is
a 25% response rate in the 10-Hz group in accordance
with 10-Hz HF-rTMS trials of reference  and 60% in
the iTBS group based on pilot studies . Assuming a
5% (bilateral) type I error and a power of 80%, a total of
60 subjects is required (calculated using SAS software).
The therapeutic response rates (proportion of
responders) in each group will be compared using a
chi-squared test (or Fisher’s exact test, if appropriate).
Estimates of absolute and relative differences (via the
odds ratio or relative risk) in terms of efficacy will be
provided with their corresponding 95% confidence
intervals. The format of the outcome data used for each
participant for analysis will be changes from baseline.
Changes in quantitative variables over time (evaluation
of the therapeutic effect of rTMS (iTBS) on variations in
the MADRS, BDI and CGI scores) will be analysed using
random effect models allowing to take into account the
repeated measurements. Time (baseline, after 5, 10, 15,
and 20 sessions, +1 month, +3 months and +6 months)
and group (iTBS or standard) effects will be estimated
and tested as well as an interaction with group. Changes
in other quantitative variables over time will be
investigated according to the same strategy.
The analysis and comparison between groups of the
onset of relapse of depression in the 6 months will be
carried out using a logistic regression model and testing
factors linked to the therapeutic response
(neuropsychological and motor tests, dimensional scales, initial
measurements of cortical excitability).
Concerning the risk of missing data, a very low
attrition rate is expected, below 5%  because of the
wellknown high tolerance to rTMS and iTBS . In case of
withdrawal of consent, patients will not be included in
final analysis – they will be replaced.
Missing data will be described in terms of frequencies
and percentage for each group. Imbalances will be
evaluated by the chi-squared test (or Fisher’s exact test).
Comparison of missing data onset during follow-up will
be realised with a log-rank test for longitudinal data.
Each dropout will be described as follows: arm, exit date,
exit reason, characteristics at inclusion and last data
collected. In case of missing data, despite every effort to
prevent it, a multiple imputation analysis will be
Depression is known as a difficult-to-treat disorder. By
2013, unipolar depression is expected to rank second
out of the 15 most common disorders after AIDS and
before ischemic heart disease . The advantages of
rTMS are numerous: it is painless, well-tolerated in
terms of memory, cardiac, hepatic and renal functions as
well as libido. There is no need for general anaesthesia
with curarisation. Since the early 1990s, an increasing
number of studies has focused on the therapeutic
potential of rTMS in psychiatry .
This technique has a compliance rate of 97% (versus
60% traditionally recorded for medication). In fact, several
meta-analyses based on randomised, controlled,
doubleblind studies refer to the therapeutic efficacy of rTMS in
the management of resistant depression. The use of rTMS
devices was also validated for this indication by the US
Food and Drug Administration (FDA) in 2008 and by the
European Union (EU) in 2012. By way of example, one of
the most recent analyses highlighted a three-fold greater
response and remission rate for left prefrontal cortex
stimulation at high frequency versus placebo .
Furthermore, once antidepressants have failed, rTMS
would be less expensive and would allow a better quality
of life and greater function compared to conventional
treatment strategies . Its mechanisms of action are
manifold: improvement in prefrontal hypometabolism
 and neuromodulation of remote cerebral areas
(especially the subgenual region) , regulation of the
hypothalamo-hypophyseal axis , modulation of
cortical excitability and synaptic plasticity [54–56] and
dopaminergic secretion [57, 58].
The optimisation of alternative treatments for
refractory or chronic depression is, therefore, a public health
issue. The Theta Burst paradigm seems promising since
3 min of iTBS are essentially more effective and have a
longer lasting effect than 20 min of conventional rTMS
stimulation at 5 Hz (as evidenced in MEPs) . In fact,
iTBS tends to mimic the physiological rhythm of the
human neocortex and involves the cerebral plasticity
mechanisms responsible for positive and presumably
longer-lasting effects , with a shorter, less intense
stimulation mechanism . Duprat et al., (2016)
recently found a 30% remission rate (HDRS <7) after
2 weeks of accelerated (20 sessions/2 weeks) iTBS in a
cross-over, sham-controlled design . These facts
suggest additional patient comfort, lower session costs and
greater prevention of relapse. In the case of a prolonged
effect, it could be an alternative to potentiating
medicinal treatment (combinations of antidepressant, mood
stabilising or adjuvant antipsychotic agents) with fewer
compliance problems. The efficacy of Theta Burst was
investigated in the management of resistant depression
in two studies, which confirmed its superiority
compared to placebo (Li et al.,  with 30 subjects; Plewnia
et al.,  involving 60 subjects). Recently, in a larger
sample but under natural conditions (retrospective
study), iTBS was as clinically effective as HF-rTMS at
10 Hz but five times longer (6 versus 30 min,
respectively) . The authors concluded that these data should
be confirmed by randomised controlled trials. Better
targeting of the responder profile leads to better use of
human and material resources in medical-economic terms.
In cognitive terms, the planning assessed in the TMT,
mental flexibility assessed using the MCST, or verbal
fluency are influenced by rTMS treatment [63–67] and are,
therefore, potential response markers. Psychomotor
retardation has a predictive value in assessing the response
for most biological treatments of depression . Unlike
cognitive functions, its pure motor component has not
been assessed objectively to date in the context of the
cerebral stimulation techniques used in the management
of depression, for instance, with tasks such as the FTT
or the prehensile motor strength test. The three main
parameters affecting the motor cortex excitability are the
CSP partly reflecting the activity of the
gammaaminobutyric acid (GABA)-B inhibitory circuits and
double-pulse measurements including: SICI partly
reflecting the activity of GABA-A IN inhibitors; and ICF
partly reflecting the activity of glutamatergic IN
activators. Two recent meta-analyses have highlighted changes
in motor cortical excitability in an entire series of
psychiatric disorders compared to healthy subjects [69, 70],
with essentially an alteration in SICI and CSP during
the depressive episode. In recent years, a few authors
have focused on their potential as response markers,
especially during noninvasive brain stimulation. In
2008, for instance, Lefaucheur et al., highlighted
interhemispheric asymmetry of cortical excitability in
depressed subjects: CSP and SICI were altered in the left
hemisphere compared to the right and contrary to
findings in healthy subjects . Following cerebral
stimulation (ECT and rTMS), Bajbouj et al. showed that CSP
and SICI improved in responders and not in
To date and to our knowledge, this is the first trial
aiming to investigate the comparative influence of iTBS
and HF-rTMS on psychomotor retardation, executive
functions and cortical motor excitability in depressed
subjects. Psychomotor retardation could be corrected by
the pro-dopaminergic effect of rTMS. Furthermore,
executive functions may be a marker of the effect of
DLPFC stimulation . Given the data available on the
effect of rTMS on magnetic resonance spectroscopy
measurements, which indicate an increase in GABA and
glutamate levels after rTMS [74, 75], neuromodulation
can be assumed to manifest in the form of changes in
cortical excitability measurements tending towards
normalisation with 10-Hz protocols and iTBS, the greatest
change being apparent in the case of the latter. The
intensity of the gabaergic and/or glutamatergic deficit(s)
and the degree of interhemispherical asymmetry in
cortical excitability tests could identify responder patient
profiles for both treatments. Moreover, measuring the
difference in neurophysiological effect in both protocols
would enhance the neurobiological understanding of this
This sample is probably not entirely representative of
a population often combining comorbidities with
considerable treatment heterogeneity. However, we opted to
limit the inclusion criteria in order to facilitate
comparison with fewer confusing variables and interpret cortical
Additional file 1: SPIRIT 2013 Checklist. recommended items to address
in a clinical trial protocol and related documents. (DOCX 52 kb)
BDI: Beck Depression Inventory; CGI: Clinical Global Impression; CSP: Cortical
Silent Period; cTBS: Continuous Theta Burst Stimulation; DLPFC: Dorsolateral
Prefrontal Cortex; e-CRF: Electronic Case Report Form; ECT: ElectroConvulsive
Therapy; ERD: Echelle de Ralentissement Dépressif; EU: European Union;
FDA: Food and Drug Administration; FTT: Finger Tapping Test;
GABA: Gamma-AminoButyric Acid; HARD scale: Humeur, Anxiété,
Ralentissement, Danger; ICF: Intracortical Facilitation; IN: InterNeurons;
iTBS: Intermittent Theta Burst Stimulation; ITT: Intention-To-Treat; L-HF:
Left-High Frequency; MADRS: Montgomery and Adsberg Rating Scale;
MCST: Modified Card Sorting Test; MEP: Motor-Evoked Potential;
MoCA: Montreal Cognitive Assessment; MRI: Magnetic Resonance Imaging;
MSM: Maudsley Staging Model; R-LF: Right-Low Frequency; RMT: Resting
Motor Threshold; rTMS: repeated Transcranial Magnetic Stimulation;
SAS: Starkstein’s Apathy Scale; SF-36: Short-Form 36; SHAPS: Snaith-Hamilton
Pleasure Scale; SICI: Short Intracortical Inhibition; TCI: Temperament and
Character Inventory; TMT: Trail Making Test; WAIS IV: Wechsler Adult
Intelligence Scale; WHO: World Health Organisation
Availability of data and materials
All supporting data can be available.
SB conceived the study and designed the study protocol and is the
coordinator of the study. SB and AS wrote the manuscript. SB, AS, EL and
J-MV are investigators and responsible for enrolment, indications for
treatment, and data collection. JF is the project manager, helped with
general organisation and sought ethical and regulatory approval. AP and
PV contributed to deliver the technique and treatment planning. VS is
responsible for statistical power calculation and analysis. TD and VTO are
responsible for designing and assessing neuropsychological status and
psychomotor retardation. EA-C is responsible for MRI data. SB, GF and YP are
responsible for cortical excitability assessment. AB is responsible for planning,
randomisation and e-CRF completion. All authors read and approved the
The authors declare that they have no competing interests.
Ethics approval and consent to participate
ANSM approval (registration number DMDPT-BLOC/MM/2014-AO1918-39/MS 1).
Nantes Ouest IV Ethics Committee approval 1 December 2015
(reference 05/15, TLT/BB CPP N°738/2015).
Information letter and consent form approved: version n°2 (12 January 2015).
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