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

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,
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.
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. ...
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]. ...
Full-text available
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 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. ...
Full-text available
Transcranial Magnetic Stimulation (TMS) has a strong evidence base for the treatment of major depressive disorder (MDD), however, there is minimal research investigating the treatment of depression within the postpartum period. This systematic review aims to systematically examine the efficacy and safety of TMS when treating postpartum depression (PPD). Databases Ovid Medline, PsycINFO, EMBASE and PubMed were searched from inception to May 2021, to identify peer-reviewed papers assessing the administration of TMS for PPD treatment. Data were systematically extracted and evaluated regarding clinical psychiatric outcomes, social-relational outcomes, neuropsychological testing, and side effects. This systematic review included one randomised controlled trial, two open-label studies, two conference papers, and two case studies, providing data on 60 participants. TMS appears well tolerated, with no reported major adverse side effects. While the studies reported a general reduction in PPD symptoms, the poor quality of the evidence available indicates that TMS for PPD is unable to be currently recommended. However, the substantial evidence for TMS in the treatment of MDD and the differential response to antidepressant medication in PPD indicates that further research into TMS for PPD is warranted.
... 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. ...
Full-text available
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% ...
Full-text available
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 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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BACKGROUND Major depressive disorder (MDD) is now the first cause of disability worldwide. So far, no validated and scalable biomarker has been identified to help with response prediction to antidepressant treatment. Cardiac biomarkers such as heart rate variability (HRV) have been studied in MDD, but few studies have examined its potential use for outcome prediction to repetitive transcranial magnetic stimulation (rTMS). OBJECTIVE We recorded pre-treatment HRV in MDD participants prior to an rTMS course. We hypothesized that higher pre-treatment HRV would be correlated with better clinical outcomes. METHODS HRV was recorded as part of a single-arm, open-label rTMS feasibility study. Pre-treatment HRV was assessed in N = 30 MDD participants before they underwent a one-week (5 days, 8 daily sessions, 40 sessions total) accelerated rTMS (arTMS) course using a low-frequency 1 Hz course (600 pulses per session, 50-minute intersession interval) over the right dorsolateral prefrontal cortex at 120% of the resting motor threshold. Clinical outcomes were captured using the Beck Depression Inventory-II (BDI-II). We tested for an association between pre-treatment HRV and clinical outcomes on the BDI-II using a linear mixed effects model. RESULTS Although average BDI-II score significantly changed over time, these changes were not significantly associated with pre-treatment HRV (p = 0.60). This finding remained when adjusting for age, sex, and HR, individually and collectively. CONCLUSION The current study did not find a relationship between pre-treatment HRV and response to low frequency rTMS. Other approaches using cardiac biomarkers may have potential for response prediction.
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Background: Treatment-resistant major depressive disorder is common; repetitive transcranial magnetic stimulation (rTMS) by use of high-frequency (10 Hz) left-side dorsolateral prefrontal cortex stimulation is an evidence-based treatment for this disorder. Intermittent theta burst stimulation (iTBS) is a newer form of rTMS that can be delivered in 3 min, versus 37·5 min for a standard 10 Hz treatment session. We aimed to establish the clinical effectiveness, safety, and tolerability of iTBS compared with standard 10 Hz rTMS in adults with treatment-resistant depression. Methods: In this randomised, multicentre, non-inferiority clinical trial, we recruited patients who were referred to specialty neurostimulation centres based at three Canadian university hospitals (Centre for Addiction and Mental Health and Toronto Western Hospital, Toronto, ON, and University of British Columbia Hospital, Vancouver, BC). Participants were aged 18-65 years, were diagnosed with a current treatment-resistant major depressive episode or could not tolerate at least two antidepressants in the current episode, were receiving stable antidepressant medication doses for at least 4 weeks before baseline, and had an HRSD-17 score of at least 18. Participants were randomly allocated (1:1) to treatment groups (10 Hz rTMS or iTBS) by use of a random permuted block method, with stratification by site and number of adequate trials in which the antidepressants were unsuccessful. Treatment was delivered open-label but investigators and outcome assessors were masked to treatment groups. Participants were treated with 10 Hz rTMS or iTBS to the left dorsolateral prefrontal cortex, administered on 5 days a week for 4-6 weeks. The primary outcome measure was change in 17-item Hamilton Rating Scale for Depression (HRSD-17) score, with a non-inferiority margin of 2·25 points. For the primary outcome measure, we did a per-protocol analysis of all participants who were randomly allocated to groups and who attained the primary completion point of 4 weeks. This trial is registered with, number NCT01887782. Findings: Between Sept 3, 2013, and Oct 3, 2016, we randomly allocated 205 participants to receive 10 Hz rTMS and 209 participants to receive iTBS. 192 (94%) participants in the 10 Hz rTMS group and 193 (92%) in the iTBS group were assessed for the primary outcome after 4-6 weeks of treatment. HRSD-17 scores improved from 23·5 (SD 4·4) to 13·4 (7·8) in the 10 Hz rTMS group and from 23·6 (4·3) to 13·4 (7·9) in the iTBS group (adjusted difference 0·103 [corrected], lower 95% CI -1·16; p=0·0011), which indicated non-inferiority of iTBS. Self-rated intensity of pain associated with treatment was greater in the iTBS group than in the 10 Hz rTMS group (mean score on verbal analogue scale 3·8 [SD 2·0] vs 3·4 [2·0] out of 10; p=0·011). Dropout rates did not differ between groups (10 Hz rTMS: 13 [6%] of 205 participants; iTBS: 16 [8%] of 209 participants); p=0·6004). The most common treatment-related adverse event was headache in both groups (10 Hz rTMS: 131 [64%] of 204; iTBS: 136 [65%] of 208). Interpretation: In patients with treatment-resistant depression, iTBS was non-inferior to 10 Hz rTMS for the treatment of depression. Both treatments had low numbers of dropouts and similar side-effects, safety, and tolerability profiles. By use of iTBS, the number of patients treated per day with current rTMS devices can be increased several times without compromising clinical effectiveness. Funding: Canadian Institutes of Health Research.
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Conventional rTMS in major depressive disorder (MDD) targets the dorsolateral prefrontal cortex (DLPFC). However, many patients do not respond to DLPFC-rTMS. Recent evidence suggests that the right lateral orbitofrontal cortex (OFC) plays a key role in 'non-reward' functions and shows hyperconnectivity in MDD. OFC-rTMS has been used successfully in obsessive-compulsive disorder, and achieved remission in an MDD case nonresponsive to DLPFC- and DMPFC-rTMS. Here, we assess the safety and tolerability of right OFC-rTMS, and examine the effectiveness of inhibitory right OFC-rTMS in MDD, particularly among patients with previous nonresponse to DMPFC-rTMS. We performed a chart review to retrieve data on clinical characteristics, stimulation parameters, adverse events, and clinical symptom outcomes for a series of 42 patients with medication-resistant and/or DMPFC-rTMS-nonresponsive MDD, who underwent 20-30 sessions of 1Hz right OFC-rTMS at a single Canadian clinic from 2015 to 2017. Over 882 sessions of treatment, there were no seizures, visual/ocular complications, or other serious or treatment-limiting adverse events. Pain ratings averaged 6-7/10 (10=maximum tolerable); no patient discontinued treatment prematurely due to pain. 15/42 patients (35.7%) achieved response (≥50% symptom reduction) and 10/42 (23.8%) achieved remission. Among the 30/42 patients who were previous nonresponders to DMPFC-rTMS, 9/30 (30.0%) achieved response and 7/30 (23.8%) achieved remission. Response distribution was sharply bimodal. 1Hz right OFC-rTMS appears safe and tolerable, and may achieve remission in MDD patients even when conventional rTMS has failed. Sham-controlled follow-up studies may be warranted.
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Background: The Canadian Network for Mood and Anxiety Treatments (CANMAT) conducted a revision of the 2009 guidelines by updating the evidence and recommendations. The scope of the 2016 guidelines remains the management of major depressive disorder (MDD) in adults, with a target audience of psychiatrists and other mental health professionals. Methods: Using the question-answer format, we conducted a systematic literature search focusing on systematic reviews and meta-analyses. Evidence was graded using CANMAT-defined criteria for level of evidence. Recommendations for lines of treatment were based on the quality of evidence and clinical expert consensus. "Neurostimulation Treatments" is the fourth of six sections of the 2016 guidelines. Results: Evidence-informed responses were developed for 31 questions for 6 neurostimulation modalities: 1) transcranial direct current stimulation (tDCS), 2) repetitive transcranial magnetic stimulation (rTMS), 3) electroconvulsive therapy (ECT), 4) magnetic seizure therapy (MST), 5) vagus nerve stimulation (VNS), and 6) deep brain stimulation (DBS). Most of the neurostimulation treatments have been investigated in patients with varying degrees of treatment resistance. Conclusions: There is increasing evidence for efficacy, tolerability, and safety of neurostimulation treatments. rTMS is now a first-line recommendation for patients with MDD who have failed at least 1 antidepressant. ECT remains a second-line treatment for patients with treatment-resistant depression, although in some situations, it may be considered first line. Third-line recommendations include tDCS and VNS. MST and DBS are still considered investigational treatments.
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The dorsolateral prefrontal cortex (DLPFC) is a common target for repetitive transcranial magnetic stimulation (rTMS) in major depression, but the conventional "5 cm rule" misses DLPFC in >1/3 cases. Another heuristic, BeamF3, locates the F3 EEG site from scalp measurements. MRI-guided neuronavigation is more onerous, but can target a specific DLPFC stereotaxic coordinate directly. The concordance between these two approaches has not previously been assessed. To quantify the discrepancy in scalp site between BeamF3 versus MRI-guided neuronavigation for left DLPFC. Using 100 pre-treatment MRIs from subjects undergoing left DLPFC-rTMS, we localized the scalp site at minimum Euclidean distance from a target MNI coordinate (X - 38 Y + 44 Z + 26) derived from our previous work. We performed nasion-inion, tragus-tragus, and head-circumference measurements on the same subjects' MRIs, and applied the BeamF3 heuristic. We then compared the distance between BeamF3 and MRI-guided scalp sites. BeamF3-to-MRI-guided discrepancies were <0.65 cm in 50% of subjects, <0.99 cm in 75% of subjects, and <1.36 cm in 95% of subjects. The angle from midline to the scalp site did not differ significantly using MRI-guided versus BeamF3 methods. However, the length of the radial arc from vertex to target site was slightly but significantly longer (mean 0.35 cm) with MRI-guidance versus BeamF3. The BeamF3 heuristic may provide a reasonable approximation to MRI-guided neuronavigation for locating left DLPFC in a majority of subjects. A minor optimization of the heuristic may yield additional concordance. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
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Background: Meta-analyses have shown that high-frequency (HF) repetitive transcranial magnetic stimulation (rTMS) has antidepressant properties when compared with sham rTMS. However, its overall response and remission rates in major depression (MD) remain unclear. Thus, we have systematically and quantitatively assessed the efficacy of HF-rTMS for MD based on randomized, double-blind and sham-controlled trials (RCTs). Method: We searched the literature from 1995 through to July 2012 using MEDLINE, EMBASE, PsycINFO, Cochrane Central Register of Controlled Trials, SCOPUS, and ProQuest Dissertations & Theses. We used a random-effects model, odds ratios (ORs) and the number needed to treat (NNT). Results: Data from 29 RCTs were included, totaling 1371 subjects with MD. Following approximately 13 sessions, 29.3% and 18.6% of subjects receiving HF-rTMS were classified as responders and remitters, respectively (compared with 10.4% and 5% of those receiving sham rTMS). The pooled OR was 3.3 (p < 0.0001) for both response and remission rates (with associated NNTs of 6 and 8, respectively). Furthermore, we found HF-rTMS to be equally effective as an augmentation strategy or as a monotherapy for MD, and when used in samples with primary unipolar MD or in mixed samples with unipolar and bipolar MD. Also, alternative stimulation parameters were not associated with differential efficacy estimates. Moreover, baseline depression severity and drop-out rates at study end were comparable between the HF-rTMS and sham rTMS groups. Finally, heterogeneity between the included RCTs was not statistically significant. Conclusions: HF-rTMS seems to be associated with clinically relevant antidepressant effects and with a benign tolerability profile.
Mood disorders cause significant morbidity and mortality, and existing therapies fail 20%-30% of patients. Deep brain stimulation (DBS) is an emerging treatment for refractory mood disorders, but its success depends critically on target selection. DBS focused on known targets within mood-related frontostriatal and limbic circuits has been variably efficacious. Here, we examine the effects of stimulation in orbitofrontal cortex (OFC), a key hub for mood-related circuitry that has not been well characterized as a stimulation target. We studied 25 subjects with epilepsy who were implanted with intracranial electrodes for seizure localization. Baseline depression traits ranged from mild to severe. We serially assayed mood state over several days using a validated questionnaire. Continuous electrocorticography enabled investigation of neurophysiological correlates of mood-state changes. We used implanted electrodes to stimulate OFC and other brain regions while collecting verbal mood reports and questionnaire scores. We found that unilateral stimulation of the lateral OFC produced acute, dose-dependent mood-state improvement in subjects with moderate-to-severe baseline depression. Stimulation suppressed low-frequency power in OFC, mirroring neurophysiological features that were associated with positive mood states during natural mood fluctuation. Stimulation potentiated single-pulse-evoked responses in OFC and modulated activity within distributed structures implicated in mood regulation. Behavioral responses to stimulation did not include hypomania and indicated an acute restoration to non-depressed mood state. Together, these findings indicate that lateral OFC stimulation broadly modulates mood-related circuitry to improve mood state in depressed patients, revealing lateral OFC as a promising new target for therapeutic brain stimulation in mood disorders.
Major depressive disorder (MDD) is a prevalent and disabling condition, and many patients do not respond to available treatments. Deep transcranial magnetic stimulation (dTMS) is a new technology allowing non-surgical stimulation of relatively deep brain areas. This is the first double-blind randomized controlled multicenter study evaluating the efficacy and safety of dTMS in MDD. We recruited 212 MDD outpatients, aged 22–68 years, who had either failed one to four antidepressant trials or not tolerated at least two antidepressant treatments during the current episode. They were randomly assigned to monotherapy with active or sham dTMS. Twenty sessions of dTMS (18 Hz over the prefrontal cortex) were applied during 4 weeks acutely, and then biweekly for 12 weeks. Primary and secondary efficacy endpoints were the change in the Hamilton Depression Rating Scale (HDRS-21) score and response/remission rates at week 5, respectively. dTMS induced a 6.39 point improvement in HDRS-21 scores, while a 3.28 point improvement was observed in the sham group (p=0.008), resulting in a 0.76 effect size. Response and remission rates were higher in the dTMS than in the sham group (response: 38.4 vs. 21.4%, p=0.013; remission: 32.6 vs. 14.6%, p=0.005). These differences between active and sham treatment were stable during the 12-week maintenance phase. dTMS was associated with few and minor side effects apart from one seizure in a patient where a protocol violation occurred. These results suggest that dTMS constitutes a novel intervention in MDD, which is efficacious and safe in patients not responding to antidepressant medications, and whose effect remains stable over 3 months of maintenance treatment.
Remission and response were suggested as the most relevant outcome criteria for the treatment of depression. There is still marked uncertainty as to what cut-offs should be used on current depression rating scales. The goal of the present study was to compare the validity of different HAMD, MADRS and BDI cut-offs for response and remission. The naturalistic prospective study was performed in 12 psychiatric hospitals in Germany. All evaluable patients (n=846) were hospitalized and had to meet DSM-IV criteria for major depressive disorder. Biweekly ratings were assessed using HAMD-21, MADRS and BDI. A CGI-S score of 1 and a CGI-I score of at least 2 was used as the primary comparative measure of remission and response, respectively. A HAMD-21 cut-off ≤7 (AUC: 0.92), HAMD-17 cut-of ≤6 (AUC: 0.90), MADRS cut-off ≤7 (AUC: 0.94) and BDI cut-off ≤12 (AUC: 0.83) were associated with a maximum of specificity and sensitivity for defining remission. A minimum decrease of 47% of the HAMD-21 (AUC: 0.90), ≤57% for HAMD-17 (AUC: 0.89), ≤ 46% for MADRS (0.91) and a decrease of 47% for the BDI baseline score (AUC: 0.78) best corresponded CGI response criteria. Our data largely confirmed currently used remission and response criteria in naturalistically treated patients.