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Current medication and transcranial magnetic stimulation (TMS) treatments for depression bring only approximately one-third of patients to remission. Newer TMS techniques such as bilateral treatment, neuronavigation, and theta burst stimulation (TBS) show promise in improving remission rates. However, it is unclear whether newer off-label techniques improve outcomes enough to justify widespread implementation.
Methods
An IRB approved retrospective chart review examined 58 primarily treatment-resistant (79%) depressed patients who received bilateral neuronavigated TBS-20Hz in a private outpatient clinic.
Results
72% (42/58) of patients remitted (Beck Depression Inventory-II (BDI-II) < 13) with an 81% decrease in BDI-II scores. 83% (48/58) of patients responded (BDI-II ≤ 50%). Average time to remission was 7.3 treatment weeks (SD = 4.5, Range 0.6–21.2). Overall, 40% (17/42) of remitters also successfully discontinued one or more pretreatment medications.
Conclusions
Bilateral Neuronavigated TBS-20Hz TMS brought more than two-thirds of treatment refractory depressed patients to remission. TBS-20Hz may be critical for obtaining higher remission rates. Controlled trials are warranted.
The antidepressant effects of TMS and medications have been demonstrated in numerous studies, but only approximately one-third of patients achieve full remission using standard protocols [
Transcranial magnetic stimulation (TMS) for major depression: a multisite, naturalistic, observational study of acute treatment outcomes in clinical practice.
]. Over the past decade, newer TMS techniques have been developed that show promise in increasing remission rates including bilateral treatment, neuronavigation, and TBS. Neuronavigation allows improved precision in locating and maintaining the proper stimulation target [
rTMS of the dorsomedial prefrontal cortex for major depression: safety, tolerability, effectiveness, and outcome predictors for 10Hz versus intermittent theta-burst stimulation.
]. Additionally, TBS applied at the particular pulse frequency of 20Hz (TBS-20Hz), rather than 50Hz (TBS-50Hz), brought more patients to remission in our clinic [
Clinical efficacy of novel 20Hz theta burst parameter in the transcranial magnetic stimulation treatment of depression brain stimulation: basic, translational, and clinical research in neuromodulation.
]. However, it is unclear whether newer TMS protocols significantly improve remission rates enough to justify their widespread adoption. We reviewed a cohort of 58 consecutive adult depression patients treated with bilateral neuronavigated TBS-20Hz to evaluate the effects of more recent off-label TMS techniques on clinical outcomes in a real-world, private practice setting.
Methods
Demographics
This IRB approved (Protocol NTBTMSDP-2017) retrospective chart review analyzed all adult depression patients presenting to our clinic for TMS depression treatment between July 1, 2013 and August 15, 2017 with a diagnosis of major depressive disorder (50), bipolar I disorder (1), bipolar II disorder (6), or schizoaffective disorder (1). Patients must have presented with moderate to severe depression (initial BDI-II score ≥ 20) [
] and completed at least 20 bilateral neuronavigated TBS-20Hz TMS treatments. The analyzed cohort consisted of thirty men and twenty-eight women with an average age of 45.3 (SD = 16.8) years. Patients were primarily treatment-resistant; 79% failed adequate trials of three or more antidepressants in two different classes. Written consent for anonymous research data collection was obtained from all patients prior to treatment.
Targeting and neuronavigation
Before beginning treatment, every patient obtained an individual 3-T T1 weighted Multi-Planar Reconstructed Magnetic Resonance Imaging (MRI) scan with 1 mm slices along all three axes. The MRI scans for each patient were imported into a Visor 2.0 Infrared Tracking Frameless Stereotaxy Neuronavigation System (ANT-Neuro, Netherlands). The MRI was segmented to obtain a three-dimensional head model of the scalp and brain and then normalized to Talairach space. Targets for the probabilistic centroid locations of left Brodmann Area 46 (−44, 40, 25) and its right-sided homolog (44, 40, 25) were marked as targets [
Cytoarchitectonic definition of prefrontal areas in the normal human cortex: II. Variability in locations of areas 9 and 46 and relationship to the Talairach Coordinate System.
]. The stimulation site was further refined by moving the magnetic field vector to the peak of the nearest gyrus and angling it perpendicularly in a posterior to anterior direction for optimal field strength [
]. The continuously active neuronavigation system was used to ensure the coil remained positioned over the target within a range of 2 mm translationally and 2° rotationally during treatments.
Motor threshold
Treatments were administered using a MagPro X-100 with MagOption and a liquid-cooled butterfly B-65 figure-eight coil. The first dorsal interosseous (FDI) muscle was used to determine the weekly bilateral resting motor threshold (MT) using electromyography (EMG). Results from single TMS pulses were analyzed with the Maximum-likelihood Strategy using Parameter Estimation by the Sequential Testing (MLS-PEST) method [
The maximum-likelihood strategy for determining transcranial magnetic stimulation motor threshold, using parameter estimation by sequential testing is faster than conventional methods with similar precision.
Patients received daily sequential bilateral treatments five days weekly. The first four-minute treatment over right dorsolateral prefrontal cortex (DLPFC) consisted of 3600–4800 continuous pulses (cTBS) using TBS-20Hz (triplet bursts with a pulse frequency of 20Hz and a burst frequency of 5Hz). The second 27-min treatment over left DLPFC consisted of 4950 intermittent pulses (iTBS) using TBS-20Hz with a 2-s stimulation interval and an 8-s inter-train interval. Earplugs were worn during the first treatment and patient-selected emotionally uplifting music was played during the second treatment. Applied magnetic field intensity was 90%–95% of each patient's ipsilateral MT. BDI-II scales were administered weekly.
Patients were treated five days weekly until remission was achieved, improvement plateaued for two consecutive weeks, or financial constraints ended treatment. Remitted patients underwent an 8-week taper phase during which the number of treatments decreased by one treatment every two weeks (4-4-3-3-2-2-1-1). Benzodiazepine use was minimized, and alcoholic beverages were prohibited during treatment. Medications were managed by each patient's psychopharmacologist.
Results
72% (42/58) of patients remitted (BDI-II<13) and 83% (48/58) of patients responded (BDI-II ≤ 50%). 60% (3/5) of patients who had failed standard TMS and 67% (2/3) of patients who had failed Electroconvulsive therapy (ECT) remitted with this protocol. Remitters had an 81% decrease in average scale scores from 35.2 (SD = 9.7) to 6.6 (SD = 4.8) (two-tailed t-test, p < .001) and non-remitters exhibited a mean 24% decrease from 40.8 (SD = 10.2) to 31.3 (SD = 12.9) (two-tailed t-test, p < .001). All patients' BDI-II scale scores decreased by an average of 63% from 36.8 to 13.6 (two-tailed t-test, p < .001). See Fig. 1A.
Fig. 1A) Shows average BDI-II scales over eighteen weeks for remitted (72%) and non-remitted (28%) depression patients during bilateral neuronavigated TBS-20Hz TMS treatment. Results include depression rating scales administered during the taper period with final scores carried forward. Because weekly rating scales were not always administered at simultaneous time points, weekly data points were interpolated linearly and then uniformly averaged at five day intervals. One treatment week is defined as five treatment days rather than seven calendar days. B) Shows the non-cumulative number of patients who remitted each treatment week, with the percentage above each bar representing that value as a percent of total treated patients.
Patients reached remission after an average of 7.3 treatment weeks (SD = 4.5, Range 0.6–21.2). Remission times were normally distributed (Kolmogorov–Smirnov test, p < .05) and 95% (40/42) of remissions occurred within two standard deviations of the mean time to remission (16.3 weeks). Cumulative interim remission rates were 26% (15/58) at six weeks and 60% (35/58) at twelve weeks. See Fig. 1B.
During preliminary (two weeks prior) and acute treatment, 3%/7%/2% and 12%/16%/5% of patients started/discontinued/started + discontinued medication(s), respectively. Overall, more patients stopped than started medications, and 40% (17/42) of remitters successfully discontinued one or more medications. There were no significant differences in age, gender, medication failures, initial BDI-II rating scores, or medication changes between remitters and non-remitters. Patients tolerated treatment well.
Discussion
Bilateral neuronavigated TBS-20Hz TMS brought over two-thirds (72%) of patients to remission with decreased seizure risk and improved tolerability due to stimulation intensities below the motor threshold. However, it is difficult to assess the most important factors contributing to the elevated remission rates. Four initial patients who failed TBS-50Hz subsequently remitted with TBS-20Hz using an otherwise identical protocol [
Clinical efficacy of novel 20Hz theta burst parameter in the transcranial magnetic stimulation treatment of depression brain stimulation: basic, translational, and clinical research in neuromodulation.
], suggesting TBS-20Hz was critical in obtaining higher remission rates. Interim remission rates demonstrate the importance of extending treatment for patients with ongoing improvement. Further TMS studies with similar treatment courses extending two standard deviations beyond the mean time to remission (capturing 95% of eventual remitters) will determine if prolonged treatment improves efficacy for other protocols. Given the possibility of significantly higher remission rates, controlled trials of bilateral neuronavigated TBS-20Hz TMS are warranted.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Declaration/conflict of interest
The corresponding author, Dr. William F. Stubbeman, has submitted a US patent application on a TMS device that uses a range of off-label pulse parameters including TBS-20Hz.
Acknowledgments
We would like to thank Dr. Harvey Sternbach for his help and support, and Dr. Jonathan Downar for his thoughtful comments.
Abbreviations
TMS
Transcranial magnetic stimulation
TBS
Theta burst stimulation
TBS-20Hz
20 Hertz Theta burst stimulation
DLPFC
Dorsolateral prefrontal cortex
BDI-II
Beck Depression Inventory-II
FDI
First dorsal interosseous
MT
Motor threshold
EMG
Electromyography
cTBS
continuous Theta burst stimulation
iTBS
intermittent Theta burst stimulation
ECT
Electroconvulsive therapy
References
Carpenter L.L.
Janicak P.G.
Aaronson S.T.
Boyadjis T.
Brock D.G.
Cook I.A.
et al.
Transcranial magnetic stimulation (TMS) for major depression: a multisite, naturalistic, observational study of acute treatment outcomes in clinical practice.
rTMS of the dorsomedial prefrontal cortex for major depression: safety, tolerability, effectiveness, and outcome predictors for 10Hz versus intermittent theta-burst stimulation.
Clinical efficacy of novel 20Hz theta burst parameter in the transcranial magnetic stimulation treatment of depression brain stimulation: basic, translational, and clinical research in neuromodulation.
Cytoarchitectonic definition of prefrontal areas in the normal human cortex: II. Variability in locations of areas 9 and 46 and relationship to the Talairach Coordinate System.
The maximum-likelihood strategy for determining transcranial magnetic stimulation motor threshold, using parameter estimation by sequential testing is faster than conventional methods with similar precision.
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