Comparative Effectiveness of Repetitive Versus Deep Transcranial Magnetic Stimulation for Major Depression: A Randomized Controlled Trial
Phase: NA
Conditions: Major Depressive Disorder
Sponsor: Centre hospitalier de l'Université de Montréal (CHUM)

 
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CLINICAL TRIAL PROTOCOL 
 
TITLE: Comparative Effectiveness of Repetitive Versus Deep Transcranial Magnetic Stimulation for 
Major Depression: A Randomized Controlled Trial 
 
CHUM project number: 2023-11389 
 
PRINCIPAL INVESTIGATOR: 
 
Jean-Philippe Miron, MD, PhD(c), FRCPC 
Unité de Neuromodulation Psychiatrique (UNP) 
Département de psychiatrie, CHUM 
Email : jean-philippe.miron.med@ssss.gouv.qc.ca 
  
CO-INVESTIGATOR: 
 
Paul Lespérance, MD, MSc, FRCPC 
Unité de Neuromodulation Psychiatrique (UNP) 
Département de psychiatrie, CHUM 
Email : paul.lesperance.med@ssss.gouv.qc.ca 
 
COLLABORATORS: 
 
François Trottier-Duclos, MD, MSc, FRCPC 
Unité de Neuromodulation Psychiatrique (UNP) 
Département de psychiatrie, CHUM 
Email : francois.trottier-duclos.cnmtl@ssss.gouv.qc.ca 
 
Didier Jutras-Aswad, MD, MSc, FRCPC 
Unité de Psychiatrie des Toxicomanies (UPT) 
Département de psychiatrie, CHUM 
Email : didier.jutras-aswad.med@ssss.gouv.qc.ca 
 
François Lespérance, MD, MBA, FRCPC 
Centre de Recherche du CHUM 
Université de Montréal 
Email : francois.lesperance.med@ssss.gouv.qc.ca 
 
Élie Bou Assi, PhD 
Centre de Recherche du CHUM 
Université de Montréal 
Email : elie.bou.assi.chum@ssss.gouv.qc.ca 
 
Dang Koha Nguyen, PhD 
Département de Neurologie 
Université de Montréal 
Email : d.nguyen@umontreal.ca 

 
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Daniel Blumberger, MD, MSc, FRCPC 
Centre for Addiction and Mental Health (CAMH), Toronto 
Email: daniel.blumberger@camh.ca 
 
Travis E. Baker, PhD 
Rutgers Center for Molecular and Behavioral Neuroscience 
Email: teb81@newark.rutgers.edu 
Martijn Arns, PhD 
Brainclinics Foundation & Maastricht University 
Email: martijn@brainclinics.com  
 
Zafiris J. Daskalakis, MD, PhD, FRCPC 
UC San Diego 
Email: zdaskalakis@health.ucsd.edu 
 
 
 
 

 
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1. THE NEED FOR A TRIAL 
1.1 The problem to be addressed 
 
Major depressive disorder (MDD) is a significant public health issue with a considerable personal 
and societal toll. MDD is estimated to affect over 300 million individuals around the globe and is now 
ranked as the leading cause of disability worldwide [1]. In Canada, the lifetime prevalence of MDD is 
12%, and ~1.9 million Canadians live with MDD in any given year [2]. First-line treatments for MDD 
include pharmacotherapy and psychotherapy [2]. Unfortunately, around 30 to 40% of patients develop 
treatment-resistant depression (TRD), classically defined as the failure to respond to one or two adequate 
trials of antidepressants [3–5]. TRD affects about ~2% of the population (~760,000 Canadians) and 
represents about 30 to 50% of the total treatment cost for MDD [6]. Given the public health imperative, 
novel therapeutic approaches are needed. 
Transcranial magnetic stimulation (TMS) has been gaining ground in the last decade for the 
treatment of TRD, with evidence of superiority over pharmacotherapy after two (2) failed antidepressant 
trials [7,8]. TMS uses rapidly alternating magnetic fields to safely stimulate specific cortical areas, 
allowing modulation of underlying dysfunctional brain networks. Even though TMS is a now well-
established treatment for TRD [9], optimizing protocols to maximize effectiveness remains an active area 
of research. 
 
The primary aim of this trial is to compare the effectiveness of two different TMS techniques 
in TRD, repetitive TMS (rTMS) and deep TMS (dTMS). Compared to rTMS, dTMS delivers a broader 
magnetic field, which in turn reduces coil positioning error and maximizes the probability of optimal 
cortical stimulation [10]. A past RCT comparing both approaches found a greater depression score 
decrease and response/remission rates for dTMS, but was short of reaching significance for remission 
rates (primary outcome) [11]. Critical components of this RCT were suboptimal, including too few 
treatment sessions and insufficient statistical power, both of which could have obscured an actual 
difference between modalities. Proof of a more effective type of TMS over another would translate 
into increased odds of improvement for TRD patients who live with a chronic and disabling illness. 
The exploratory aim of this trial is to study the predictive value of candidate biomarkers for 
TMS in MDD. Two scalable techniques have shown the potential to develop biomarkers in pilot studies: 
electroencephalography (EEG) and electrocardiography (ECG). These highly scalable approaches could 
easily be implemented in regular clinical psychiatric settings. Predicting an individual's chances of 
improvement to TMS before the start of treatment could expedite remission, spare futile 
interventions, and protect limited clinical resources. 
The results of this trial will have clinically significant benefits for MDD patients. Evidence of the 
superiority of dTMS could lead to more favorable clinical outcomes for patients suffering from TRD and 
offer an additional treatment option to individuals who have not responded to rTMS. Identifying scalable 
biomarkers ready for clinical use could also positively impact the care trajectory of patients suffering 
from TRD and reduce the current trial-and-error approach for treatment selection. 
1.2 Research questions 
Primary: To assess the superiority of dTMS over rTMS in TRD. 
Hypothesis: dTMS will achieve significantly greater reduction in depressive symptoms and higher 
response/remission rates than rTMS. 
Exploratory: To evaluate the predictive capacity of scalable candidate biomarkers. 
Hypothesis: Specific biomarker features at baseline will predict response to TMS overall, irrespective of 
the specific TMS modality. 
1.3 The need for a trial 
1.3.1 The need to increase the effectiveness of TMS for TRD 
 
 
The evidence for the effectiveness of TMS in TRD is supported by well over 200 RCTs and 
dozens of meta-analyses [5,9,12]. Health Canada approved TMS in 2002, and U.S. Food and Drug 
Administration (FDA) followed suit for TRD in 2008. The most recent literature indicates that TMS 

 
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consistently achieves response (≥50% improvement from baseline) and remission (little to no symptoms 
left) rates of 40-55% and 25-35% in TRD, respectively [5]. TMS involves the use of a powerful alternating 
magnetic field to modulate neuronal activity. Electromagnetic pulses are delivered through coils of 
various designs. Standard rTMS uses figure-8 coils offering focal and superficial stimulation [13]. Even 
though rTMS is effective in TRD, remission rates are still below those for electroconvulsive therapy 
(ECT), which remains the gold standard for TRD [14]. Given the low patient acceptability of ECT [15], 
work must continue to optimize the effectiveness of therapies such as TMS, which possess an 
advantageous safety, tolerability, and acceptability profile [5]. 
1.3.2 Rationale for testing the clinical efficacy between dTMS and rTMS 
Several ways to increase the effectiveness of TMS have been studied, including increasing the 
number of pulses per session, various frequencies, bilateral treatment, treatment acceleration, and 
functional imaging. So far, none have yielded consistent results [16–24]. One approach of interest has been 
to improve coil technology [25]. Figure-8 coils used for rTMS have been developed for neurophysiological 
experimentation, where more focus stimulation is preferred for precise target engagement. Unfortunately, 
the high individual variability of the prefrontal cortex (PFC) and the probabilistic nature of figure-8 coil 
positioning renders them theoretically more prone to error in clinical use. Neuronavigation systems have 
been developed to optimize targeting [26], but these tools are expensive and technically complex, currently 
precluding widespread use. 
H-coils used in dTMS, on the other hand, were developed for specifically for clinical use (Fig. 1 
of the Appendix). H-coils create a much broader and deeper magnetic field than figure-8 coils, reducing 
coil positioning error and maximizing the probability of optimal cortical stimulation. Indeed, even though 
the average thickness of the cortical gray matter strip is only 2 mm, the highly convoluted pattern of 
organization (gyri and sulci) means that some parts of the gray matter may remain sub-optimally 
stimulated with figure-8 coils compared to H-coils. H-coils are, therefore, better adapted to engage the 
underlying PFC circuitry. The initial H-coil developed for TRD was the H1. More recently, another H-
coil has received FDA clearance for MDD: the H7 [27]. The H7 has the advantage of stimulating 4x deeper 
than figure-8 coils (compared to 2.5x for the H1-coil), translating into a total stimulated brain volume of 
40.3 cm3 for the H7, compared to 18 cm3 for the H1, and only 3 cm3 for figure-8 coils. Because of this, 
the H7 can stimulate large portions of the PFC, including the dorsolateral and dorsomedial prefrontal 
regions. These areas, which are of significant interest in MDD [28], can only be simultaneously stimulated 
by the H7. The clinical advantage of broader PFC stimulation provided by dTMS is supported by the 
effectiveness of ECT, which causes widespread whole-brain depolarization. ECT still, to this day, 
remains the gold standard in terms of clinical outcomes in TRD, with remission rates of ~50%, according 
to the most recent data [14]. The recruitment of larger PFC areas by dTMS may therefore be expected 
to augment the antidepressant effect.  
Because of this, some have theorized the therapeutic superiority of dTMS over rTMS in MDD 
[29]. While some evidence suggests this [11], the issue is still vigorously debated. Resolving this research 
question is vital to enhance the effectiveness of TMS for TRD. 
1.3.3 rTMS vs. dTMS 
 
dTMS was shown to be effective for TRD in its landmark trial [30]. Subsequently, an RCT 
compared rTMS (N = 75) and dTMS (N = 72) in a way that led to inconclusive findings [11]. Even though 
the proportion of remitters was greater in the dTMS group (dTMS 60% remission, CI95% 48–71%; 
rTMS 43% remission, CI95% 31–55%), this was not statistically significant (OR 1.74, CI95% 0.79–
3.83, p = 0.17). Regarding secondary endpoints, response was significantly greater with dTMS (OR 2.33, 
CI 95% 1.04–5.21, p = 0.040). The 17-item Hamilton Rating Scale for Depression (HRSD-17) decrease 
was also significantly greater in the dTMS group (p = 0.048). Still, this trial was underpowered and only 
used a limited 20-session course, which is insufficient [31] and probably prevented full therapeutic effects. 
These equivocal results require a well-designed and appropriately powered head-to-head RCT. 
Such a trial would be vital to improving the overall effectiveness of TMS and guide the 

 
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implementation and choices of optimal technology in clinical settings. Additionally, this trial did not 
follow up with patients beyond the treatment period (4 weeks). It is now established that trajectories of 
outcomes vary between individuals treated with TMS and that some do not reach a plateau of 
improvement by treatment end [32] and can continue to improve afterward [33]. Research health metrics 
such as functioning and quality of life may also require longer follow-up periods.   
 
Lastly, that trial used the original 10 Hz stimulation protocol initially approved by the FDA for 
rTMS. More recently, intermittent theta burst stimulation (iTBS) has been introduced for rTMS and 
received FDA approval. The landmark iTBS-rTMS trial (THREE-D study co-chaired by DMB and ZJD) 
established the non-inferiority of this approach to the 10 Hz stimulation protocol [18]. iTBS is delivered 
in only ~3 min, compared to 37.5 min for 10 Hz, which makes it much more efficient (time-saving and 
cost-effective) and has led to its adoption by many clinics worldwide [34]. 
1.3.4 The search for biomarkers 
 
In addition to treatment optimization, biomarkers are another key strategy in improving outcomes 
in MDD. Predicting the chances of improvement to TMS before the start of the procedure could help 
treatment centers better orient patients to optimal therapies, spare them futile interventions and improve 
the use of limited clinical resources. Encouraging results have emerged from neuroimaging studies [35], 
but scalable, reliable, and cost-effective candidates are needed [36]. This work aligns with our group's 
expertise in TMS and biomarkers [33,37–49]. 
 
Individual alpha frequency: EEG biomarkers have shown great promise in MDD 35,48,49.  EEG 
has the advantage of being a low-cost, broadly available, and already established tool in routine clinical 
care 48. Initial studies suggested pathologic frontal alpha asymmetry in MDD [50], and interference with 
this abnormal rhythm by TMS has been theorized to reset dysfunctional thalamocortical oscillators and 
lead to therapeutic improvement [51]. A research question arising from this observation has been 
determining if specific TMS stimulation frequencies are more efficient at interfering with these abnormal 
rhythms. It was initially determined in a pilot study that participants (N = 35) undergoing rTMS 
experienced a greater improvement when their individual alpha frequency (iAF) was closer to the 10 Hz 
[52]. Collaborator MA on this proposal later replicated this finding in a larger cohort (N = 59) [53]. 
So far, this promising approach remains to be explored with other frequencies, such as those proposed 
here (18 Hz/dTMS and iTBS/rTMS). Such evidence could help clinicians assign patients to an optimal 
TMS protocol based on their iAF, an example of the recently-discussed Stratified Psychiatry concept [36]. 
Our hypothesis is that individuals with baseline iAF closer to 10 Hz will respond better to TMS 
overall.  
 
Reward positivity: EEG event-related potentials (ERPs) are also recognized as promising 
biomarkers. Decreased reward positivity (REWP), an ERP elicited by reward feedback, is associated 
with MDD [58]. REWP originates from the anterior cingulate and is highly sensitive to insults to the 
mesocorticolimbic reward system [58–61]. REWP has been shown to reflect the anterior cingulate 
electrophysiological response to dopaminergic reward prediction error signals [60,62]. A substantial body 
of evidence implicates dopamine and anterior cingulate dysfunction in MDD and a series of studies 
demonstrated that REWP amplitude can serve as a biomarker for depression [58]. Importantly, TMS 
applied to the PFC can enhance dopamine release, neuronal activity, and cerebral blood flow in the 
cingulate cortex [63–66]. We previously demonstrated that 10 Hz rTMS applied to the DLPFC 
enhanced REWP in substance users [45,46]. In healthy subjects, we demonstrated that 600 pulses of 
iTBS applied to the left DLPFC suppressed the amplitude of REWP across two independent studies 
[47]. To date, the effects of dTMS on REWP amplitude are unknown, which adds to the innovation of the 
proposed work. Since REWP studies have shown the cingulate is critically involved in MDD [58,59], it 
may be hypothesized that a similar mode of action involving the cingulate, as measured by the REWP, 
is the case in the treatment of MDD. REWP is thus well-positioned to serve as an RDoC-type predictive 
biomarker of reward-related psychopathology in MDD. While other ERPs have been studied in MDD, 
REWP has the most extensive literature supporting its use in the context of cingulate dysfunction and 

 
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MDD. In line with this work, we hypothesize that a TMS-induced modulation of cingulate activity could 
be objectively evaluated using REWP, particularly for a condition with mesocorticolimbic reward system 
dysfunction like MDD. Our hypothesis is that participants with lower baseline REWP will respond 
better to TMS overall. 
 
ECG: Cardiac function abnormalities and autonomic nervous system dysfunctions have been 
extensively described in MDD, focusing on decreased vagal control, which could represent a failure of 
the PFC to inhibit sympathetic activity [67]. At the neurobiological level, subcortical hyperactivity is 
thought to be responsible for increased sympathetic tone in response to stress [68]. The PFC regulates 
sympathetic and parasympathetic activity by top-down mechanisms through the vagus nerve via the 
subgenual anterior cingulate [67]. In MDD, these mechanisms could be compromised, given the known 
dysfunctions of the PFC in MDD. Since TMS is theorized to normalize PFC activity, its effects could 
therefore be captured by cardiac activity recording [69]. ECG-based biomarkers represent a low-cost and 
scalable approach that merits further investigation. Our team has already shown that greater baseline 
ECG corrected QT interval length was associated with greater improvement in vagus nerve stimulation 
[38] and that even though baseline resting-state heart rate variability was not associated with improvement 
to TMS [49], lower baseline resting-state heart rate (HR) was associated with greater improvement [70]. 
Our hypothesis is that participants with higher baseline corrected QT interval and lower baseline 
resting-state HR will respond better to TMS overall. 
1.4 Knowledge transition 
 
We will engage in knowledge translation with the scientific and clinical communities via 1) 
publication of study findings in high-impact peer-reviewed open-access journals with a broad readership 
and 2) presentations at international scientific conferences, including both leading neuroscience (e.g., 
Society of Biological Psychiatry, American College of Neuropsychopharmacology), brain stimulation 
(e.g., International Brain Stimulation Conference), national (e.g., Canadian Psychiatric Association) and 
provincial (Association des Médecins Psychiatres du Québec) annual meetings. We will also summarize 
our findings in plain language and use media deemed to be highly effective for knowledge users. We will 
also disseminate our findings via social media platforms. Knowledge translation will also be facilitated 
through our members’ affiliation and collaboration with the Réseau Québécois sur le suicide, les troubles 
de l’humeur et les troubles associés. We will liaise with radio, television, and press journalists to ensure 
media coverage of this study and its potential benefits. The media and federal and provincial 
governmental organizations frequently solicit our research team members for their expertise. Information 
that identifies participants or that reasonably could be used to identify participants will not be included 
in such publications. A timeline of our planned knowledge translation activities is provided in Table 
1 of the Appendix. 
1.5 Risk management 
 
TMS is a well-tolerated procedure with limited side effects and a well-established safety track 
record [71,72]. Both rTMS and dTMS systems are approved by Health Canada. For most patients, adverse 
events are minimal, the most common side effects being mild discomfort at the stimulation site and 
mild headaches/fatigue after stimulation (20-30%). Nausea, irritability, and sleep disturbance are rarely 
seen (< 5%) [71]. Seizures are the most severe potential adverse event reported with TMS but are 
extremely rare (0.01%, ten times lower than antidepressants) [71]. No difference in adverse events (types 
or frequency) has been reported between rTMS and dTMS [11], an observation supported by our pilot 
data. Standard operating procedures regarding the emergence of side effects are in place, including a 
specific procedure in the event of a seizure/loss of consciousness, which mobilizes the blue code team. 
Regarding adverse events monitoring, we will follow the same protocol as in the THREE-D study [18]. 
At each session, participants will be queried for any suicidal ideation and adverse events. All adverse 
events will be recorded for analysis. Participants will also report pain levels to the TMS procedure on a 
verbal analog scale (from 1 [no pain] to 10 [intolerable pain]). We will also record the number of serious 
adverse events and reasons for treatment discontinuation when such events occur. A psychiatrist will 

 
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always be available in case of adverse events, assessment of emergent/worsening suicidal ideation, or 
any other emergencies. 
2. THE PROPOSED TRIAL 
 
2.1 Recruitment 
 
Potential participants will be selected among regular clinical patients referred by their medical 
doctor via the secretariat of the psychiatric neuromodulation clinic of the CHUM (email: 
neuromodulation.psychiatrie.chum@ssss.gouv.qc.ca, tel: 514-890-8000 #26489, fax: 514 412-7792), or 
by their medical doctor via the lab website (www.labo-unp.ca). As part of the clinical routine 
administrative functioning, a clinical nurse will contact all patients referred for neuromodulation 
treatments and evaluate them. The nurse will then schedule a medical appointment with one of the 
psychiatrists of the study. If the participant meets eligibility criteria, the psychiatrist will offer to the 
patient to participate in the study. If the participant is interested, the research coordinator will contact 
the participant to describe the study and the treatment (treatment schedule), side effects as well as to 
answer any question the participant might have. The research coordinator will then schedule an 
appointment with the participant to obtain informed consent.  
 
2.2 Design 
The trial will now be conducted as a randomized, single-center, two-arm, parallel-group pilot 
study, primarily aimed at assessing feasibility and preliminary outcomes involving 50 adult outpatients 
with TRD over two (2) years starting in January 2024. Using a computerized random permuted block 
method, participants will be randomly allocated (1:1) to one of the two intervention groups (rTMS or 
dTMS). Before the study initiation, we will obtain written approval from the Research Ethics Board, and 
this protocol will be registered on clinicaltrials.gov. 
2.3 Interventions 
 
After consent and enrollment, patients will undergo a screening visit to obtain demographic, 
clinical, and baseline data to determine their eligibility for the trial according to inclusion and exclusion 
criteria (section 2.5 below). Participants will be randomized to receive either rTMS on a MagPro X100 
research grade stimulator (MagVenture) equipped with a B70 fluid-cooled coil or dTMS on a research 
Brainsway system equipped with an H7-Coil. Following randomization, patients will undergo baseline 
assessments and motor threshold testing to determine the appropriate site and strength of stimulation 
according to standard methods, and then begin treatment [18,30,73]. For dTMS, the MDD FDA-cleared 18 
Hz stimulation protocol will be used (2 sec ON, 20 sec OFF, 55 trains; 1980 pulses per session; 20 min 
10 s duration; 120% hand motor threshold [27]). For rTMS, the MDD FDA-approved iTBS protocol will 
be used (triplet 50 Hz bursts repeated at 5 Hz, 2 s ON and 8 s OFF; 600 pulses per session; total duration 
of 3 min 9 s, 120% hand motor threshold [18]). 
2.4 Randomization 
 
Subjects will be randomized into the study and stratified by treatment failure, defined by the 
failure to two adequate trials vs. those with more than two adequate trial failures, as assessed by an 
Antidepressant Treatment History Form (ATHF) score of more than 3 in the current episode [74]. The 
degree of treatment resistance has been a significant predictor of improvement in treatment in prior TMS 
trials. It is essential to ensure that the groups are balanced for this variable [75–77]. Randomization will be 
based on a stratified permuted block design, using random block sizes to decrease the likelihood of 
predictability of group assignments. An independent statistician external to the study will manage the 
computer-generated randomization list. Research staff will not have access to the randomization 
schedule. 
2.5 Blinding 
 
Given the study's design, blinding participants and TMS operators will not be possible. Still, staff 
responsible for participant assessments and data analysis will be blinded to treatment conditions and 

 
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external to the clinic staff. Patients will be instructed not to reveal their group assignment to the raters. 
Patients will not be given the specifics of the treatment parameters and will be instructed not to talk to 
each other during the study period. Both treatments will be presented as effective to them. Lastly, the 
data management center will strictly control access to the randomization code. 
2.5 Eligibility criteria 
 
Inclusion criteria: Adults aged 21–70 years with a Mini-International Neuropsychiatric Interview 
(MINI)-confirmed  diagnosis of  MDD [78], at least moderate intensity, single or recurrent episode, 
HRSD-17 score of at least 18 [18,79], no improvement to at least two adequate courses of antidepressants 
(based on the ATHF) or were unable to tolerate at least two separate trials of antidepressants of 
inadequate dose and duration, and have been on a stable antidepressant regimen for the past four weeks 
before screening. Patients with a chronic depressive episode >2 years and who have previously received 
ECT or ketamine will be eligible to participate. 
 
Exclusion criteria: Having previously received TMS; substance use disorder within the last three 
months; diagnosis of bipolar or psychosis spectrum disorder; anxiety or personality disorder that is 
assessed by a study investigator to be the primary cause and causing greater impairment than MDD; 
concomitant major unstable medical or neurological illness, intracranial implant, cardiac pacemaker or 
implanted medication pump; significant laboratory abnormality; active suicidal intent; pregnancy; if 
participating in psychotherapy, must have been in stable treatment for at least three months before entry 
into the study, with no anticipation of change; currently taking more than the equivalent of 2 mg of 
lorazepam of a benzodiazepine daily or any dose of an anticonvulsant due to the potential to limit TMS 
effectiveness. If participants do take benzodiazepines, they will be instructed not to take them before 
treatment, only after and no later than at bedtime. 
 
Discontinuation criteria: Participants will be withdrawn if: i) they experience worsening in 
depression, defined as an increase in HRSD-17 from baseline of more than 25% during two consecutive 
assessments, or development of active suicidal intent or attempted suicide; ii) the Principal Investigator 
believes that for safety reasons, it is in the best interest of the participant to stop participation. 
Discontinued participants will receive whichever treatment plan is optimal for their situation. Participants 
will be permitted to miss scheduled treatment days due to illness or scheduling conflicts, and sessions 
will be added to complete the scheduled 30 sessions. However, participants who miss four consecutive 
treatment days will be excluded from the study, although we will attempt to continue collecting outcome 
data. 
2.6 Treatment period duration 
 
Participants will undergo one (1) daily treatment session over six (6) consecutive weeks (Monday 
to Friday) for a total of 30 sessions, which is the standard in TMS studies [31]. 
2.7 Frequency and duration of follow-up 
 
Biomarkers will be acquired at baseline (W0). Clinical measures will be completed at W0, 
immediately post-treatment on the last day (W6), and at follow-ups post-treatment: 1-week (W7), 4-week 
(W10), 12-week (W18).  
2.8 Outcomes 
Primary: (1) dTMS and rTMS score changes from baseline to W6 on the HRSD-17 scale; (2) Response 
(yes/no) defined as a reduction ≥50% on the HRSD-17 scale from baseline to W6; (3) Remission (yes/no) 
defined as a score ≤ 7 on the HRSD-17 scale at W6. 
Secondary: dTMS and rTMS score changes, response, and remission at other timepoints (W7, W10, and 
W18); outcomes on other symptomatic scales (see below in section 2.9 clinical assessments), global 
measures of severity/improvement and quality of life and functionality; tolerability, self-reported adverse 
events, treatment-associated pain, numbers of all-cause dropouts. 
Exploratory: iAF, REWP, resting-stage ECG features, and NCG-TMS pupil measures at baseline. 
2.9 Assessments (see Table 2 of the Appendix) 

 
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Clinical assessments: The primary outcome measure will be measured by the HRSD-17, which 
has been the standard scale in both TMS and pharmacotherapy trials in TRD for decades [18]. Other scales 
include the HRSD-28, Hamilton Anxiety Rating Scale (HAMA) [80], 16-Item Quick Inventory of 
Depressive Symptomatology Self-Report (QIDS-SR-16) [81], General Anxiety Disorder-7 (GAD-7) [82], 
Snaith–Hamilton Pleasure Scale (SHAPS) [83], Columbia-Suicide Severity Rating Scale (C-SSRS) [84], 
Rumination Response Scale (RRS), Adult ADHD Self-Report Scale [85], The McLean Screening 
Instrument for Borderline Personality Disorder (MSI-BPD) [86] and various cognitive tests (see Table 2 
of the Appendix). At each session, participants will be queried for any suicidal ideation and adverse 
events, which will be recorded for analysis. Participants will also report pain levels to the TMS procedure 
on a verbal analog scale (from 1 [no pain] to 10 [intolerable pain]). We will also record the number of 
serious adverse events and reasons for treatment discontinuation when such events occur. Medical 
history, an electrocardiogram (ECG), blood tests, BMI, vital signs, and urine analysis (including drug 
screen) will be obtained at baseline. 
Biomarker assessments: Biomarkers will be collected at baseline. Participants will also undergo 
resting state ECG and EEG recordings using standard procedures [87,88]. EEG recording will be acquired 
through a 32-channel device (Natus Trex HD with video). In line with previous investigations [53], resting 
state EEG will be recorded for 5 minutes with eyes closed followed by 5 minutes with eyes open while 
the subject fixates on a red dot on a screen. Participants will be asked to stay relaxed during the 
acquisition, and electrooculogram (EOG) electrodes will be installed to record eye movements. Skin 
impedance will be maintained below 10 kW for all electrodes. EEG recordings will be sampled at 512 
Hz. Following resting-state EEG, recording will continue during the completion of the Probabilistic 
Selection Task, a well-established reward task that elicits robust REWP and is believed to be sensitive to 
dopamine and reward functioning [46]. REWP is measured by subtracting the amplitude (in microvolts) 
of the EEG reward-related potentials from non-reward-related potentials.  
Brain Vision Analyzer 2.0 will be used to process EEG recordings. 1) Preprocessing: 
Preprocessing will be undertaken to filter EEG recordings and remove artifacts and discontinuities. Finite 
impulse response Butterworth filters will be used to bandpass EEG recordings into the frequency band 
of interest (0.3-100 Hz). A notch filter will be implemented to reject powerline interferences (60 Hz). 
The forward-backward technique will keep the signals’ phase intact [89]. By filtering the input EEG data 
in both the forward and reverse directions, this method allows to perform zero-phase digital filtering with 
no phase distortion and thus preserves features in the filtered time-series at precisely the same timepoint 
on which they occur on the unfiltered time series. The Autoreject algorithm will be used for artifact 
detection and correction. This adaptive method uses cross-validation to identify an optimal peak-to-peak 
amplitude threshold. In addition, the Gratton technique (regression-based) will be used to EOG-correct 
the data. Finally, data will be re-referenced to the average reference; 2) Segmentation: Resting state 
EEG recordings will be segmented into non-overlapping windows of 4 s epochs; 3) Feature extraction: 
In line with previous investigations within the context of TMS outcome prediction, iAF will be calculated 
for electrodes F3 and F4 during eyes closed resting states [52,53]. Power spectrum will be evaluated by 
applying a Fast Fourier Transform to 4 s EEG epochs (50% overlap, Hamming window), where iAF 
corresponds to the maximum value on the power spectrum within the alpha frequency range (7-13 Hz). 
Patients with no clear/dominant iAF will be excluded from the analysis. A dominant iAF frequency will 
be defined as a maximum value within the alpha frequency range higher than 1.5 Z-score below the 
mean. The proportion of excluded subjects (those who do not show a dominant iAF) will be compared 
to those reported in Corlier and colleagues (15.1%) and Roelofs and colleagues (12.6%) [52,53].   
Regarding pupil measure procedures, they will follow what was described in a recent study[91]. 
All recordings will be obtained through a pupillometer NeurOptics PLR-3000 (NeurOptics Inc., Irvine, 
ca, USA). Pupil data will be obtained from both eyes. No calibration is required, and data will be stored 
on the device with results uploadable to an external computer.  
2.10 Sample size 

 
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In light of budget constraints, we revised our study design to accommodate a smaller sample size, 
aligning it with the scope of a pilot study. The original plan to recruit 220 participants (110 per group) 
was based on calculations that assumed a 3-point difference in change from baseline between groups on 
the HRSD-17 scale and a standard deviation of 7.5 for the change in HRSD-17 in each group. These 
calculations suggested that 198 patients (99 per group) would be necessary to determine if dTMS is 
superior to rTMS with 80% power and a 5% two-sided significance level [88], adjusted for an anticipated 
attrition rate of up to 10% [18]. However, due to a lower than expected budget, we have revised our 
sample size to a total of 50 participants, with 25 in each group. This reduction necessitates a 
reclassification of the study as a pilot study. Pilot studies are valuable for testing the feasibility of larger 
trials, refining study protocols, and providing preliminary data. While the smaller sample size may limit 
the power to detect the originally hypothesized effect size, it remains sufficient for exploring trends and 
generating hypotheses. The findings from this pilot study will be crucial for informing the design and 
sample size calculations of subsequent, larger-scale trials. 
2.11 Quality of life and health service research metrics 
 
Patient functioning and quality of life is an increasingly recognized aspect of improvement with 
antidepressant treatment. The following scales will be measured at baseline and follow-ups. The Clinical 
Global Impression Severity/Improvement (CGI-S, CGI-I) scales will be used as a global measure of 
severity and improvement [93]. Quality of life will be assessed by the World Health Organization Quality 
of Life Short Version (WHOQOL-BREF) [94] and functionality by the Sheehan Disability Scale (SDS) 
[95]. 
2.12 Planned recruitment rate 
 
It is anticipated that a timeline of 5 years will be necessary to complete all facets of the proposed 
trial (the study timeline is presented in Table 1 of the Appendix). Given significant outreach efforts 
in the past six months and our new partnerships with nearby hospitals, we have averaged 6.5 new referrals 
per week, which would lead to ~340 new referrals per year. On average, >75% of referrals to our clinic 
are accepted for treatment. If we expect at least 25% of those patients to be eligible and accept 
participating in the trial, we are confident that recruitment will proceed at a rate of at least ~15 participants 
per trimester, reaching the target of 220 participants over the 4-year enrollment period. 
2.13 Compliance 
 
Dropout rates to TMS in the literature and at our clinic are less than 5% [18], but we used a more 
conservative 10% for sample size calculation. 
2.14 Loss to follow-up 
 
Attrition rate to TMS in the literature and at our clinic for the 1-month follow-up is less than 5% 
[18]. Active strategies to reduce dropout and attrition rates will be employed, such as calls by the study 
team in case of no show and reminders for upcoming follow-ups. 
2.15 Number of centers involved 
 
This will be a single-center trial. Even though a multicenter trial would accelerate recruitment 
and study completion, we are unaware of any other academic research institution with rTMS 
(MagVenture) and dTMS (Brainsway) equipment and who would be available to collaborate on this 
project. We have the necessary infrastructure to carry out the trial successfully. 
2.16 Statistical analyses 
 
We sought a statistical consultation at our research center for this section, and a biostatistician 
will be responsible for the statistical plan and analyses. The primary analysis will follow the intent-
to-treat principle. To assess if dTMS is superior to rTMS, an analysis of covariance (ANCOVA) will be 
performed, with the HRSD-17 total score at W6 as the outcome. Independent variables will include the 
treatment attribution (rTMS or dTMS), the HRSD-17 score at baseline and the stratification variable 
(treatment failure to 2 trials or >2 antidepressant trials). ANCOVAs are known to have more power and 
increased precision in an RCT context over ANOVA [96]. Additionally, it is often recommended to adjust 
for the stratification variables in the primary analysis, especially for moderately sized trials [97,98]. 

 
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Estimates for the mean difference between groups will be produced with the corresponding 95% 
confidence interval. Also, rates of response and remission (as defined in section 2.8) between the 
intervention groups will be compared using chi-squared tests. As secondary analysis, a generalized linear 
mixed model (GLMM) will be used to analyze repeated measures of study outcomes (HRSD-17 score, 
response, and remission) for timepoints of interest (W6, W7, W10, and W18) while accounting for the 
HRSD-17 score at baseline [99]. The model will include time, treatment group and their interaction as 
fixed effects. Different structures of variance-covariance matrix will be considered, but one will be 
selected based on the Akaike Information Criterion [100]. 
Subsequently, biomarkers distribution by sex and age group will be described using mean, 
standard deviation, median and interquartile ranges. Univariate generalized linear models (GLM) will 
be used to assess whether, individually, baseline biomarkers predict changes in HRSD-17 post-TMS for 
each timepoint [101]. A multivariate GLM will also be used to evaluate the ability of all baseline 
biomarkers to accurately predict changes in HRSD-17 when used together. Potential confounders such 
as sex and age will be included in the multivariate regression model. Correlations between biomarkers 
will be assessed using a spearman correlation matrix. Stratified analysis per treatment group will be 
conducted to verify the hypothesis that baseline biomarkers are predictors of changes in HRSD-17 
regardless of the treatment received (rTMS or dTMS). Finally, we will investigate the relationship 
between the biomarkers and the response using the set of analyses described above with appropriate 
adjustments for categorical outcome. 
2.17 Frequency of analyses 
 
While no interim analyses are planned, the final analyses at the conclusion of this pilot study will 
be instrumental in determining the feasibility and potential trends indicating the efficacy of the 
interventions. Should these results demonstrate promising trends, they will serve as a foundation for 
seeking additional funding and designing a larger-scale study to further investigate these findings. 
2.18 Planned subgroup analyses considering sex and gender 
 
We are planning a subgroup analysis to investigate sex-based differences in outcomes between 
the two treatment groups in analyses stratified by sex [102]. In addition, we will include measures of gender 
identity, gender role identification, and sexual orientation. We will perform preliminary and exploratory 
analyses to begin addressing the knowledge gap regarding the effect of these variables in MDD. Our 
team includes a CIHR Sex and Gender Science Chair who will guide us through these analyses. 
2.19 Has any pilot study been carried out using this design? 
 
We compared preliminary clinical outcomes of 63 TRD patients who received (1) rTMS-iTBS 
[N=28], (2) dTMS-H1 [N=17], (3) dTMS-H7 [N=16] using the clinician-rated MADRS scale. Our 
preliminary results suggest greater therapeutic effects for dTMS-H7 compared to the two other 
modalities. Average percent improvement for the dTMS-H7 group was 34.4% (SD 35.3), while it was 
26.1% (SD 29.9) for the dTMS-H1 group and 23.2% (SD 25.3) for the rTMS-iTBS group. There is a 
similar trend using the self-rated BDI-II. All TMS modalities were well-tolerated, with no difference 
between groups regarding adverse events or dropout rates. This preliminary data supports our hypothesis 
that larger coils can have increased therapeutic effects, with the more significant effects mediated by the 
H7, which generates the most extensive electromagnetic field. 
 
Fig. 2 of the Appendix outlines biomarker pilot data gathered for this proposal. In summary, 
it was determined by one of our collaborators (MA) that patients with an iAF closer to 10 Hz experienced 
greater improvement (Fig. 2A). Our group also recently reported the potential predictive role of resting-
state baseline HR to TMS (Fig. 2B) [70]. We also determined that a higher corrected QTc interval on 
baseline ECG predicted response to TMS (Fig. 2C) [38].  
3. TRIAL MANAGEMENT 
3.1 Trial management 

 
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The trial will be conducted at the Centre Hospitalier de l'Université de Montréal (CHUM), which 
has a high recruitment capacity and is configured for maximal collaboration between clinical and 
research teams. Trial management procedures will leverage existing staff and infrastructures at our brain 
stimulation clinic. Our research center (Centre de Recherche du CHUM - CRCHUM), a unique hospital-
based research center incorporating basic, preclinical, clinical, and public health research, will provide 
research support. CRCHUM’s methodological and statistical platform (CITADEL) will provide 
statistical expertise and data monitoring/management services and was involved in the methodological 
design and statistical planning of the proposed study. This capacity includes the generation of 
randomization tables and clinical outcome data collection via a RedCap server hosted at CITADEL with 
web-accessible, privacy-compliant input of patient data on-site. 
 
3.2 Ethical considerations  
 
Source documents will always be kept in a locked filing cabinet to limit access, and in the case 
of electronic source documents, files will be password-protected and saved in a secure CHUM or 
CRCHUM server. However, our case report forms (CRF’s) will not contain any personal health 
information. Only the subject number will be recorded in the CRF, and if the subject name appears on 
any other document (e.g. laboratory report), it must be obliterated on the copy of the document retained 
in the Trial Master File or made available for audit. Study data will be kept for 10 years after the end of 
the study, in accordance with data protection laws. Subjects will be informed that representatives of other 
parties (including pharmaceutical companies), ethics committee (IEC)/institutional review board (IRB) 
or regulatory authorities may inspect their records to verify the information collected, and that all 
personal information made available for inspection will be handled in the strictest confidence and in 
accordance with data protection laws. The investigator will maintain an encrypted and password 
protected personal subject identification list (subject numbers with the corresponding subject names) to 
enable records to be identified and retrieved. 
3.3 Team and applicants 
 
The research team is led by NPA and ECR Jean-Philippe Miron (MD, PhD; 10hrs/week), brain 
stimulation psychiatrist, and research director of the CHUM's Unité de Neuromodulation Psychiatrique 
(UNP). Paul Lespérance (MD, MSc; 10hrs/wk) is a brain stimulation psychiatrist and founder of the 
CHUM's UNP. Both will be responsible for participant recruitment and management. Daniel M. 
Blumberger (MD, MSc; 1hr/wk) is a clinician scientist at the Centre for Addiction and Mental Health in 
Toronto with solid expertise in clinical trials of TMS for MDD. All three have expertise in TRD and 
brain stimulation RCTs, have contributed to the trial design and characterization, and will ensure that 
clinical trial guidelines, regulations, and procedures are met. Didier Jutras-Aswad (MD, MSc; 1hr/wk) 
will further assist in RCT regulations and policies locally. Élie Bou Assi (PhD; 1hr/wk - EEG), Dang 
Khoa Nguyen (MD, PhD; 1hr/wk - EEG), Travis E. Baker (PhD; 1hr/wk – EEG and REWP), Martijn 
Arns (PhD; 1hr/wk – EEG and NCG-TMS), Zafiris J. Daskalakis (MD, PhD; 1hr/wk) will assist in the 
biomarker aspects of the study, quality control, and biomarker data analysis.  
3.4 Trial steering committee 
 
The trial steering committee will be composed of Dr. Miron, Dr. Lespérance, and two outside 
experts with complementary knowledge of TMS/TRD/trials/methodology/statistics and will meet two 
times a year. The committee will monitor and discuss the following: recruitment, device management, 
budgets, consent procedures, consent forms, safety plans before study initiation, monitoring of the 
progress of the study, retention of subjects, adverse events, serious adverse events, reasons for participant 
withdrawal, adherence to the timeline of the study, quality of data, protocol violation and make directives 
about the continuation, modification, or termination of the study (based on the balance of adverse events 
and beneficial outcomes). Throughout the study, notification of any SAEs and proposed investigator-
initiated protocol changes will be submitted to the committee for further evaluation. A Data and Safety 
Monitoring Board will not be necessary since we use TMS equipment already approved by Health 

 
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Canada. Lastly, our trial management group (executive committee), composed of Dr. Miron, Dr. 
Lespérance, our research coordinator will meet every two weeks. 
 
 
3.5 Funding 
One-year grant of 100'000 CAD from the Canadian Institutes of Health Research (CIHR).  
 
 
 

 
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