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A case series of a novel 1 Hz right-sided dorsolateral prefrontal cortex rTMS protocol in major depression

Authors:
A case series of a novel 1 Hz right-sided dorsolateral prefrontal cortex rTMS protocol in
major depression
Jean-Philippe Miron 1,2,3,4,5,,*, Helena Voetterl 1,6,, Farrokh Mansouri 1,2,3, Daniel M. Blumberger
3,4,7, Zafiris J. Daskalakis 3,4,7 and Jonathan Downar 1,2,3,4.
1 Krembil Research Institute, University Health Network, Toronto, ON, Canada;
2 Poul Hansen Family Centre for Depression, University Health Network, Toronto, ON, Canada;
3 Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, ON, Canada;
4 Department of Psychiatry, Faculty of Medicine, University of Toronto, Toronto, ON, Canada;
5 Unité de Neuromodulation Psychiatrique (UNP), Centre Hospitalier de l’Université de Montréal
(CHUM), Université de Montréal, Montréal, QC, Canada;
6 Department of Cognitive Neuroscience, Maastricht University, Maastricht, Limburg,
Netherlands;
7 Temerty Centre for Therapeutic Brain Intervention at the Centre for Addiction and Mental
Health, Toronto, ON, Canada.
Equal authorship
* Corresponding author
Word count: 1003
Figures: 1
KEYWORDS: Treatment-Resistant Depression; TRD; Transcranial Magnetic Stimulation; TMS;
circular coil; DLPFC
To the Editor,
Although effective in treatment-resistant depression (TRD) and superior in tolerability to
medication, repetitive transcranial magnetic stimulation (rTMS) is currently burdened by high
costs of equipment acquisition, operation and technical complexity, precluding its widespread
use [1]. Simplifying the treatment technique could facilitate more widespread uptake of rTMS in
community settings. To this end, we investigated a non-cooled parabolic coil that is less
expensive than cooled figure of eight (Fo8) coils and allow simplified positioning because of its
central opening and wide stimulation area.
Between August 2018 and June 2019, 43 TRD patients completed at least fifteen (15)
sessions of 1 Hz right-sided dorsolateral prefrontal cortex (DLPFC) rTMS at our clinic using a
MagPro R30 and a MMC-140 parabolic coil (MagVenture, Farum, Denmark). Patient selection
process is described in our previous reports [2,3]. All patients provided informed consent and
this study was approved by the Research Ethics Board of the University Health Network.
Patients underwent once-daily right DLPFC-rTMS, with the center of the coil over F4
(calculated using a right-flipped adjusted BeamF3 algorithm [4]) for 15-30 sessions, 5
times/week (1 Hz, 60 s on and 30 s off, 6 trains, 8.5 min total stimulation time, 360 pulses/day
[5]), at 120% of resting motor threshold for the hand muscles. Patients completed a Beck
Depression Inventory - II (BDI-II) before every treatment session. Response was defined as an
improvement of 50% from baseline; remission was defined as a final treatment score 12 [6].
Overall, 43 patients underwent treatment (mean course length 22.4 ± 5.9 sessions) for a
total 979 sessions in this series. Regarding baseline characteristics, mean age was 40.6 ± 13.3,
with 63% female patients. Mean pre-treatment BDI-II was 36.4 ± 10.0. Number of previous
failed medication trials averaged 1.8 ± 1.5, and length of current episode 37.5 ± 54.9 months.
42 patients had a diagnosis of unipolar depression, 1 patient had bipolar depression and 20
(46.5 %) patients had a comorbid anxiety disorder.
No serious adverse events occurred. All patients experienced manageable pain levels,
with reported VAS scores ranging from 1 to 7 (VAS scale 1-10, 10 = maximum tolerable pain).
First-session mean pain rating was 6.5 ± 1.9, decreasing to 5.0 ± 2.4 by the final session. No
patient discontinued prematurely due to pain or any other adverse symptoms such as
headache, fatigue or vertigo. Mean motor threshold (MT) was 37.2 ± 9.0% of maximal stimulator
output. Average treatment intensity (120% of MT) was 44.1 ± 9.0%, with 2.3 ± 3.8 days to reach
target intensity.
Sixteen of the 43 patients (37.2%) achieved response (50% improvement from
baseline) and 10/43 (23.3%) achieved remission (mean improvement, 32.9% ± 31.8).
Responders showed steady improvement to maximal effect at their final week of treatment (Fig.
1A). An Epanechnikov kernel with band width of 15%, probability density estimate of the percent
improvement revealed a trimodal distribution of outcomes (Fig. 1B), with a notch near 50%
improvement, distinguishing a responsive subgroup (50 to 70%) from a non-responsive
subgroup (20 to 30%), similar to our previous reports [3]. Another notch around 0%
distinguished non-responders from a third group having experienced slight deterioration (-10 to
-20%) with treatment. Comparing deteriorating with non-deteriorating patients using
independent-samples t-test and logistic regression analysis wielded no statistically significant
differences (p < 0.05) in baseline characteristics (sex, age, comorbid anxiety, duration of the
depressive episode and number of medication). No association was also found between these
and response (p < 0.05).
To our knowledge, this is the first case series investigating the use of a parabolic coil
with 1 Hz stimulation in patients with MDD. The current results are superior to what was
reported in one of our recently published study [3] and in the classic and highly cited meta-
analysis of high-frequency (HF) rTMS by Berlim et al [7]. While encouraging, those results are
below what was reported in a large randomized controlled trial (RCT) by our group [8].
The main goal of this study was to test the use of this novel coil design. With
conventional Fo8 coils, targeting requires expertise, since scalp landmarks are hidden under the
coil. Due to its central opening, this coil allows for direct visualization of the landmarks, and
hence easier placement (Fig. 1C). This could potentially facilitate the delivery of rTMS in a wider
range of settings. The use of 1 Hz stimulation likewise facilitates more widespread use of rTMS
since it can be delivered on inexpensive stimulators.
Of note, the magnetic field is weaker in the central area of the parabolic coil, where the
opening is located (Fig. 1D). This raises the possibility that centering the coil over DLPFC could
in fact lead to less DLPFC stimulation and more stimulation of adjacent regions such as lateral
orbitofrontal cortex. Notably, stimulation of this area with rTMS [2] and intracortical electrodes
[9] has been shown to decrease depressive symptoms. Another study has also shown efficacy
of larger coils in TRD [10]. Placement of the parabolic coil more medially, to enhance
stimulation of DLPFC proper, may be worth future study.
An interesting and novel observation is the presence of patients who seem to have
experienced a deterioration in their mood with this protocol. This was not seen in previous
studies [2,3]. If replicated, this could warrant another study to determine if there are any
predictors of this trajectory of outcome.
Limitations of this case series include the use of only patient-rated scales, heterogeneity
of comorbidities and medications, and are similar to another case series from our group [3].
In summary, this series suggests that 1 Hz right DLPFC-rTMS delivered with parabolic
coils is safe, well tolerated, and effective in MDD patients with mild to moderate TRD. Although
the positioning of this coil might bear future optimization, the simplicity of the technique and its
applicability via low-cost equipment could greatly expand the reach of rTMS beyond specialized
centers in developed countries. Given the widespread global burden of MDD, more affordable,
scalable, and simplified rTMS techniques could markedly enhance the delivery and overall
impact of the technique on patient health around the world.
CONFLICTS OF INTEREST
HV and FM report no conflicts of interest. JPM reports research grants from the Brain &
Behavior Research Foundation NARSAD Young Investigator Award and salary support for his
graduate studies from the Branch Out Neurological Foundation. JD reports research grants from
CIHR, the National Institute of Mental Health, Brain Canada, the Canadian Biomarker
Integration Network in Depression, the Ontario Brain Institute, the Weston Foundation, the
Klarman Family Foundation, the Arrell Family Foundation, and the Buchan Family Foundation,
travel stipends from Lundbeck and ANT Neuro, in-kind equipment support for investigator-
initiated trials from MagVenture, and is an advisor for BrainCheck, TMS Neuro Solutions, and
Restorative Brain Clinics. DMB has received research support from the CIHR, NIH, Brain
Canada and the Temerty Family through the CAMH Foundation and the Campbell Research
Institute. He received research support and in-kind equipment support for an investigator-
initiated study from Brainsway Ltd., and he is the principal site investigator for three sponsor-
initiated studies for Brainsway Ltd. He received in-kind equipment support from Magventure for
investigator-initiated research. He received medication supplies for an investigator-initiated trial
from Indivior. He has participated in an advisory board for Janssen. In the last 5 years, ZJD has
received research and equipment in-kind support for an investigator-initiated study through
Brainsway Inc and Magventure Inc. His work was supported by the Ontario Mental Health
Foundation (OMHF), the Canadian Institutes of Health Research (CIHR), the National Institutes
of Mental Health (NIMH) and the Temerty Family and Grant Family and through the Centre for
Addiction and Mental Health (CAMH) Foundation and the Campbell Institute.
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... rTMS was delivered through MagPro R20 stimulators equipped with parabolic MMC-140 coils (MagVenture, Farum, Denmark). We recently published a case series on the safety, tolerability, and effectiveness of those coils in MDD (Miron et al., 2019). The resting motor threshold (rMT) was determined according to standard clinical practice, with the additional need to use the coil's middle ring for stimulation, where the electromagnetic field strength is at its highest (McClintock et al., 2017;Miron et al., 2019). ...
... We recently published a case series on the safety, tolerability, and effectiveness of those coils in MDD (Miron et al., 2019). The resting motor threshold (rMT) was determined according to standard clinical practice, with the additional need to use the coil's middle ring for stimulation, where the electromagnetic field strength is at its highest (McClintock et al., 2017;Miron et al., 2019). We used a previously published 1 Hz rTMS protocol (60 s on and 30 s off, 6 trains, 8.5 min total stimulation time, 360 pulses/sessions, 120% rMT) over the right dorsolateral prefrontal cortex (DLPFC) with the coil centred on the F4 EEG location (using the BeamF3 algorithm, but on the right-side of the head) (Brunelin et al., 2014;Miron et al., 2019). ...
... The resting motor threshold (rMT) was determined according to standard clinical practice, with the additional need to use the coil's middle ring for stimulation, where the electromagnetic field strength is at its highest (McClintock et al., 2017;Miron et al., 2019). We used a previously published 1 Hz rTMS protocol (60 s on and 30 s off, 6 trains, 8.5 min total stimulation time, 360 pulses/sessions, 120% rMT) over the right dorsolateral prefrontal cortex (DLPFC) with the coil centred on the F4 EEG location (using the BeamF3 algorithm, but on the right-side of the head) (Brunelin et al., 2014;Miron et al., 2019). Treatment consisted of an arTMS course of 6 sessions/day (50 min inter-sessions intervals) over 5 days (on weekdays), thus totalling 30 sessions. ...
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Although effective in major depressive disorder (MDD), repetitive transcranial magnetic stimulation (rTMS) is costly and complex, limiting accessibility. To address this, we tested the feasibility of novel rTMS techniques with cost-saving opportunities, such as an open-room setting, large non-focal parabolic coils, and custom-built coil arms. We employed a low-frequency (LF) 1 Hz stimulation protocol (360 pulses per session), delivered on the most affordable FDA-approved device. MDD participants received an initial accelerated rTMS course (arTMS) of 6 sessions/day over 5 days (30 total), followed by a tapering course of daily sessions (up to 25) to decrease the odds of relapse. The self-reported Beck Depression Inventory II (BDI-II) was used to measure severity of depression. Forty-eight (48) patients completed the arTMS course. No serious adverse events occurred, and all patients reported manageable pain levels. Response and remission rates were 35.4% and 27.1% on the BDI-II, respectively, at the end of the tapering course. Repeated measures ANOVA showed significant changes of BDI-II scores over time. Even though our protocol will require further improvements, some of the concepts we introduced here could help guide the design of future trials aiming at increasing accessibility to rTMS.
... rTMS was delivered through MagPro R20 stimulators equipped with parabolic MMC-140 coils (MagVenture, Farum, Denmark). We recently published a case series on the safety, tolerability, and effectiveness of those coils in MDD [20]. The resting motor threshold (rMT) was . ...
... The copyright holder for this preprint this version posted June 17, 2020. . determined according to standard clinical practice, with the additional need to use the coil's middle ring for stimulation, where the electromagnetic field strength is at its highest [20,21]. We 1-month follow-up visits were conducted 1-month (± 7 days) after the last tapering session. ...
... Parabolic coils also allow simplification of rTMS delivery. We previously published a case report on their use [20], delineating their potential advantage over Fo8 coils. Indeed, large parabolic coils may require less precise placement given their large electromagnetic field compared to the target brain region -a factor also present with larger helmet-shaped coils [31]. ...
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BACKGROUND Repetitive transcranial magnetic stimulation (rTMS) is effective in major depressive disorder (MDD). However, technical complexity and operational costs might have been barriers for its wide use and implementation in some jurisdictions, thereby decreasing accessibility. OBJECTIVE Our main goal was to test the feasibility of a novel rTMS protocol optimized for practicality, scalability and cost-effectiveness. We hypothesized that our novel rTMS protocol would be simple to implement and well-tolerated, but less costly and allow for more treatment capacity. METHODS Treatment was administered in an open-room setting, allowing a single technician to attend to multiple patients. Large non-focal parabolic coils held by custom-built arms allowed simple yet efficient and accurate placement. We employed a low-frequency (LF) 1 Hz stimulation protocol (360 pulses per session), delivered on the most affordable FDA-approved devices. MDD participants received an initial accelerated rTMS course (arTMS) of 6 sessions/day over 5 days (30 total), followed by a tapering course of daily sessions (up to 25) to decrease the odds of relapse. The self-reported Beck Depression Inventory II (BDI-II) was used to measure severity of depression. RESULTS Forty-eight (48) patients completed the arTMS course. No serious adverse events occurred, and all patients reported manageable pain levels. Response and remission rates were 35.4% and 27.1% on the BDI-II, respectively, at the end of the tapering course. CONCLUSION If rTMS could be delivered for lower cost at higher volume, while preserving efficacy, safety and tolerability, it could warrant further investigation of this treatment as a first-line intervention in MDD. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT04376697
... The proposed aim of rTMS is to either stimulate or inhibit regions of the neural cortex [39]. Studies have found lower magnetic frequencies (≤1 Hz) create an inhibitory effect, and higher frequencies (>5 Hz) create an enhancing effect [39][40][41][42][43]. The meta-analysis of imaging studies and rTMS by Taib et al. [39] reports there are multiple brain structures involved in the pathophysiology of MDD including; amygdala; dorsolateral prefrontal cortex (DLPFC); ventrolateral and ventromedial PFC; hippocampus; the anterior cingulate cortex (ACC); inferior frontal cortex; and basal ganglia. ...
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... Parabolic coils could be a solution to this and have just started to be studied using safe and effective 1 Hz protocols. 67,68 Their central opening allows for direct visualization of scalp landmarks and therefore easier and more reliable positioning. Their shape also fits the natural curvature of the head and their large stimulation area could decrease the need for precise positioning. 1 Hz stimulation also has the advantage to only require basic stimulators that do not require cooling, further decreasing costs. ...
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Repetitive transcranial magnetic stimulation (rTMS) is a safe and well-tolerated intervention for major depressive disorder (MDD). Over 150 randomized controlled trials (RCTs) have been carried out, and its efficacy has been confirmed in dozens of meta-analyses. Real world data has also confirmed the effectiveness of rTMS for MDD in clinical practice, with the most recent literature indicating response rates of 40–50% and remission rates of 25–30%. In this review, we first offer an historical perspective, followed by a review of basic principles, such as putative mechanisms, procedures and protocols, stimulation targets, efficacy and durability of response, side effects, and the placebo controversy. In the second part of this review, we first discuss solutions to increase accessibility to rTMS, such as modifications to treatment equipment, protocols and setting. We continue with possible means to further increase effectiveness, such as treatment personalization and extension. We conclude by addressing the scheduling issue, with accelerated rTMS (arTMS) as a possible solution.
... Compared to that study, we modified our 1 Hz protocol to increase the number of pulses and daily sessions, in order to potentially maximize treatment effects, switched to a standard figure-8 coil to increase generalizability, and also reassessed at 4 weeks posttreatment without any maintenance or continuation treatment to study if treatment effect could be maintained through time. As in our previous study, response rates at 1 week after treatment were lower than what is usually reported in meta-analyses of standard once-daily rTMS trials ( Lefaucheur et al., 2020 ;Miron et al., 2019 ), even though the responders subgroup had achieved response on average by the last day of treatment ( Fig. 2 ). This changed 4 weeks after treatment, where there was a noticeable increase in responders and remitters, reaching 43.3% and 30.0% ...
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BACKGROUND Repetitive transcranial magnetic stimulation (rTMS) is an effective intervention in major depressive disorder (MDD) but requires daily travel to a treatment clinic over several weeks. Shorter rTMS courses retaining similar effectiveness would thus increase the practicality and scalability of the technique, and therefore its accessibility. OBJECTIVE We assessed the feasibility of a novel 5 day accelerated 1 Hz rTMS protocol. We hypothesized that this novel rTMS protocol would be safe and well-tolerated while shortening the overall treatment course. METHODS We conducted a prospective, single-arm, open-label feasibility study. Thirty (30) participants received a one-week (5 days) accelerated (8 sessions per day, 40 sessions total) course of 1 Hz rTMS (600 pulses per session, 50-minute intersession interval) over the right dorsolateral prefrontal cortex (R-DLPFC) using a figure-of-eight coil at 120% of the resting motor threshold (rMT). Primary outcomes were response and remission rates on the Beck Depression Inventory-II (BDI-II). RESULTS Response and remission rates 1 week after treatment were 33.3% and 13.3% respectively and increased to 43.3% and 30.0% at follow-up 4 weeks after treatment. No serious adverse events occurred. All participants reported manageable pain levels. CONCLUSION 1 Hz rTMS administered 8 times daily for 5 days is safe and well-tolerated. Validation in a randomized trial will be required. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT04376697.
... Indeed, 1 Hz rTMS only requires very basic stimulators, which could be much more affordable than usual setups required for HF and Deep TMS. Our group also recently published a case series on easy-of-use non-cooled non-focal parabolic coils [10]. These could be an affordable alternative to cooled coils, while also offering a solution to targeting issues given their non-focality. ...
... Treatments typically require a TMS operator to hold a TMS coil over the left dorsolateral prefrontal cortex (DLPFC) to noninvasively pass electromagnetic pulses into this brain region that is under-activated in depression. A recent variant of this treatment for depression is using 360 pulses of daily low frequency (1Hz) rTMS to the right DLPFC, with the specific intention of evaluating this treatment paradigm for at-home administration (5). Preliminary results using this approach have been promising, with 37.2% of patients having a 50% or greater reduction in depression symptoms after four weeks of daily treatments(5). ...
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