Brigitte Zrenner1, Christoph Zrenner1, Pedro Caldana Gordon2, Paolo Belardinelli1, Eric J McDermott1, Surjo R Soekadar3, Andreas J Fallgatter4, Ulf Ziemann5, Florian Müller-Dahlhaus6. 1. Department of Neurology and Stroke, And Hertie Institute for Clinical Brain Research, Eberhard Karls University Tübingen, Germany. 2. Department of Neurology and Stroke, And Hertie Institute for Clinical Brain Research, Eberhard Karls University Tübingen, Germany; Service of Interdisciplinary Neuromodulation, Laboratory of Neuroscience (LIM27) and National Institute of Biomarkers in Psychiatry (INBioN), Department and Institute of Psychiatry, Hospital Das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil. 3. Department of Psychiatry and Psychotherapy, Eberhard Karls University Tübingen, Germany; Clinical Neurotechnology Laboratory, Neuroscience Research Center (NWFZ) & Department of Psychiatry and Psychotherapy, Charité - University Medicine Berlin, Germany. 4. Department of Psychiatry and Psychotherapy, Eberhard Karls University Tübingen, Germany. 5. Department of Neurology and Stroke, And Hertie Institute for Clinical Brain Research, Eberhard Karls University Tübingen, Germany. Electronic address: ulf.ziemann@uni-tuebingen.de. 6. Department of Neurology and Stroke, And Hertie Institute for Clinical Brain Research, Eberhard Karls University Tübingen, Germany; Department of Psychiatry and Psychotherapy, Johannes Gutenberg University Medical Center Mainz, Germany.
Abstract
BACKGROUND:Repetitive transcranial magnetic stimulation (rTMS) of the left dorsolateral prefrontal cortex (DLPFC) is an effective treatment for major depressive disorder (MDD), but response rates are low and effect sizes small. Synchronizing TMS pulses with instantaneous brain oscillations can reduce variability and increase efficacy of TMS-induced plasticity. OBJECTIVE: To study whether brain oscillation-synchronized rTMS is feasible, safe and has neuromodulatory effects when targeting the DLPFC of patients with MDD. METHODS: Using real-time EEG-triggered TMS we conducted a pseudo-randomized controlled single-session crossover trial of brain oscillation-synchronized rTMS of left DLPFC in 17 adult patients with antidepressant-resistant MDD. Stimulation conditions in separate sessions were: (1) rTMS triggered at the negative EEG peak of instantaneous alpha oscillations (alpha-synchronized rTMS), (2) a variation of intermittent theta-burst stimulation (modified iTBS), and (3) a random alpha phase control condition. RESULTS: Triggering TMS at the negative peak of instantaneous alpha oscillations by real-time analysis of the electrode F5 EEG signal was successful in 15 subjects. Two subjects reported mild transient discomfort at the site of stimulation during stimulation; no serious adverse events were reported. Alpha-synchronized rTMS, but not modified iTBS or the random alpha phase control condition, reduced resting-state alpha activity in left DLPFC and increased TMS-induced beta oscillations over frontocentral channels. CONCLUSIONS: Alpha-synchronized rTMS of left DLPFC is feasible, safe and has specific single-session neuromodulatory effects in patients with antidepressant-resistant MDD. Future studies need to further elucidate the mechanisms, optimize the parameters and investigate the therapeutic potential and efficacy of brain oscillation-synchronized rTMS in MDD.
RCT Entities:
BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) of the left dorsolateral prefrontal cortex (DLPFC) is an effective treatment for major depressive disorder (MDD), but response rates are low and effect sizes small. Synchronizing TMS pulses with instantaneous brain oscillations can reduce variability and increase efficacy of TMS-induced plasticity. OBJECTIVE: To study whether brain oscillation-synchronized rTMS is feasible, safe and has neuromodulatory effects when targeting the DLPFC of patients with MDD. METHODS: Using real-time EEG-triggered TMS we conducted a pseudo-randomized controlled single-session crossover trial of brain oscillation-synchronized rTMS of left DLPFC in 17 adult patients with antidepressant-resistant MDD. Stimulation conditions in separate sessions were: (1) rTMS triggered at the negative EEG peak of instantaneous alpha oscillations (alpha-synchronized rTMS), (2) a variation of intermittent theta-burst stimulation (modified iTBS), and (3) a random alpha phase control condition. RESULTS: Triggering TMS at the negative peak of instantaneous alpha oscillations by real-time analysis of the electrode F5 EEG signal was successful in 15 subjects. Two subjects reported mild transient discomfort at the site of stimulation during stimulation; no serious adverse events were reported. Alpha-synchronized rTMS, but not modified iTBS or the random alpha phase control condition, reduced resting-state alpha activity in left DLPFC and increased TMS-induced beta oscillations over frontocentral channels. CONCLUSIONS: Alpha-synchronized rTMS of left DLPFC is feasible, safe and has specific single-session neuromodulatory effects in patients with antidepressant-resistant MDD. Future studies need to further elucidate the mechanisms, optimize the parameters and investigate the therapeutic potential and efficacy of brain oscillation-synchronized rTMS in MDD.
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