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

2019; Elsevier BV; Volume: 13; Issue: 2 Linguagem: Inglês

10.1016/j.brs.2019.11.006

1935-861X

Jean‐Philippe Miron, Helena Voetterl, Farrokh Mansouri, Daniel M. Blumberger, Zafiris J. Daskalakis, Jonathan Downar,

Pain Management and Treatment

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]Milev R.V. Giacobbe P. Kennedy S.H. Blumberger D.M. Daskalakis Z.J. Downar J. et al.Canadian Network for mood and anxiety treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder.Can J Psychiatr. 2016; 61: 561-575https://doi.org/10.1177/0706743716660033Crossref PubMed Scopus (220) Google Scholar]. 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]Feffer K. Fettes P. Giacobbe P. Daskalakis Z.J. Blumberger D.M. Downar J. 1Hz rTMS of the right orbitofrontal cortex for major depression: safety, tolerability and clinical outcomes.Eur Neuropsychopharmacol. 2017; https://doi.org/10.1016/j.euroneuro.2017.11.011Crossref PubMed Scopus (31) Google Scholar,[3]Miron J.-P. Feffer K. Cash R.F.H. Derakhshan D. Kim J.M.S. Fettes P. et al.Safety, tolerability and effectiveness of a novel 20 Hz rTMS protocol targeting dorsomedial prefrontal cortex in major depression: an open-label case series.Brain Stimul. 2019; 12: 1319-1321https://doi.org/10.1016/j.brs.2019.06.020Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar]. 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]Mir-Moghtadaei A. Caballero R. Fried P. Fox M.D. Lee K. Giacobbe P. et al.Concordance between BeamF3 and MRI-neuronavigated target sites for repetitive transcranial magnetic stimulation of the left dorsolateral prefrontal cortex.Brain Stimul. 2015; 8: 965-973https://doi.org/10.1016/j.brs.2015.05.008Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar]) 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]Brunelin J. Jalenques I. Trojak B. Attal J. Szekely D. Gay A. et al.The efficacy and safety of low frequency repetitive transcranial magnetic stimulation for treatment-resistant depression: the results from a large multicenter French RCT.Brain Stimul. 2014; 7: 855-863https://doi.org/10.1016/j.brs.2014.07.040Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar]), 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]Riedel M. Möller H.-J. Obermeier M. Schennach-Wolff R. Bauer M. Adli M. et al.Response and remission criteria in major depression--a validation of current practice.J Psychiatr Res. 2010; 44: 1063-1068https://doi.org/10.1016/j.jpsychires.2010.03.006Crossref PubMed Scopus (165) Google Scholar]. 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 bandwidth 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 (50–70%) from a non-responsive subgroup (20–30%), similar to our previous reports [[3]Miron J.-P. Feffer K. Cash R.F.H. Derakhshan D. Kim J.M.S. Fettes P. et al.Safety, tolerability and effectiveness of a novel 20 Hz rTMS protocol targeting dorsomedial prefrontal cortex in major depression: an open-label case series.Brain Stimul. 2019; 12: 1319-1321https://doi.org/10.1016/j.brs.2019.06.020Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar]. 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]Miron J.-P. Feffer K. Cash R.F.H. Derakhshan D. Kim J.M.S. Fettes P. et al.Safety, tolerability and effectiveness of a novel 20 Hz rTMS protocol targeting dorsomedial prefrontal cortex in major depression: an open-label case series.Brain Stimul. 2019; 12: 1319-1321https://doi.org/10.1016/j.brs.2019.06.020Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar] and in the classic and highly cited meta-analysis of high-frequency (HF) rTMS by Berlim et al. [[7]Berlim M.T. van den Eynde F. Tovar-Perdomo S. Daskalakis Z.J. Response, remission and drop-out rates following high-frequency repetitive transcranial magnetic stimulation (rTMS) for treating major depression: a systematic review and meta-analysis of randomized, double-blind and sham-controlled trials.Psychol Med. 2014; 44: 225-239https://doi.org/10.1017/S0033291713000512Crossref PubMed Scopus (274) Google Scholar]. While encouraging, those results are below what was reported in a large randomized controlled trial (RCT) by our group [[8]Blumberger D. Vila-Rodriguez F. Thorpe K. Feffer K. Noda Y. Giacobbe P. et al.Effectiveness of theta burst versus high-frequency repetitive transcranial magnetic stimulation in patients with depression (THREE-D): a randomised non-inferiority trial.The Lancet. 2018; 391: 1683-1692https://doi.org/10.1016/S0140-6736(18)30295-2Abstract Full Text Full Text PDF PubMed Scopus (260) Google Scholar]. 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]Feffer K. Fettes P. Giacobbe P. Daskalakis Z.J. Blumberger D.M. Downar J. 1Hz rTMS of the right orbitofrontal cortex for major depression: safety, tolerability and clinical outcomes.Eur Neuropsychopharmacol. 2017; https://doi.org/10.1016/j.euroneuro.2017.11.011Crossref PubMed Scopus (31) Google Scholar] and intracortical electrodes [[9]Rao V.R. Sellers K.K. Wallace D.L. Lee M.B. Bijanzadeh M. Sani O.G. et al.Direct electrical stimulation of lateral orbitofrontal cortex acutely improves mood in individuals with symptoms of depression.Curr Biol. 2018; : 1-25https://doi.org/10.1016/j.cub.2018.10.026Abstract Full Text Full Text PDF Scopus (44) Google Scholar] has been shown to decrease depressive symptoms. Another study has also shown efficacy of larger coils in TRD [[10]Levkovitz Y. Isserles M. Padberg F. Lisanby S.H. Bystritsky A. Xia G. et al.Efficacy and safety of deep transcranial magnetic stimulation for major depression: a prospective multicenter randomized controlled trial.World Psychiatry. 2015; 14: 64-73https://doi.org/10.1002/wps.20199Crossref PubMed Scopus (176) Google Scholar]. 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]Feffer K. Fettes P. Giacobbe P. Daskalakis Z.J. Blumberger D.M. Downar J. 1Hz rTMS of the right orbitofrontal cortex for major depression: safety, tolerability and clinical outcomes.Eur Neuropsychopharmacol. 2017; https://doi.org/10.1016/j.euroneuro.2017.11.011Crossref PubMed Scopus (31) Google Scholar,[3]Miron J.-P. Feffer K. Cash R.F.H. Derakhshan D. Kim J.M.S. Fettes P. et al.Safety, tolerability and effectiveness of a novel 20 Hz rTMS protocol targeting dorsomedial prefrontal cortex in major depression: an open-label case series.Brain Stimul. 2019; 12: 1319-1321https://doi.org/10.1016/j.brs.2019.06.020Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar]. 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]Miron J.-P. Feffer K. Cash R.F.H. Derakhshan D. Kim J.M.S. Fettes P. et al.Safety, tolerability and effectiveness of a novel 20 Hz rTMS protocol targeting dorsomedial prefrontal cortex in major depression: an open-label case series.Brain Stimul. 2019; 12: 1319-1321https://doi.org/10.1016/j.brs.2019.06.020Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar]. 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 .