Exploration of NMDA and GABA receptor-mediated plasticity induced by 10-Hz repetitive transcranial magnetic stimulation
6 affiliations
- 1Brain Stimulation Mechanisms Laboratory, Division of Depression and Anxiety Disorders, McLean Hospital, Belmont, MA, 02478, USA
- 2Department of Psychiatry, Harvard Medical School, Boston, MA, 02115, USA
- 3Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Butler Hospital, Providence, RI, 02903, USA
- 4Department of Clinical Science, Kaiser Permanente Bernard J. Tyson School of Medicine, Pasadena, US
- 5Brain Stimulation Mechanisms Laboratory, Division of Depression and Anxiety Disorders, McLean Hospital, Belmont, MA, 02478, USA. [email protected]
- 6Department of Psychiatry, Harvard Medical School, Boston, MA, 02115, USA. [email protected]
Abstract
Although 10-Hz repetitive transcranial magnetic stimulation (rTMS) is an FDA-approved treatment for depression, we do not understand the mechanisms through which rTMS induces therapeutic change. Two competing theories suggest that 10-Hz rTMS induces N-methyl-D-aspartate receptor (NMDAR)-dependent long-term potentiation (LTP), and/or removal of inhibitory gamma-aminobutyric acid receptors (GABARs). We examined these two proposed mechanisms of action in the human motor cortex in a double-blind, randomized, four-arm crossover study in six healthy subjects. We tested plasticity with motor-evoked potentials (MEPs) and learning with serial reaction time task (SRTT) before and after 10-Hz rTMS in the presence of four drugs separated by 1 week each: placebo, d-cycloserine (DCS 100 mg), DCS 100 mg + NMDAR partial antagonist dextromethorphan (DXM 150 mg), and lorazepam (LZP 2.5 mg). NMDAR agonism by DCS enhanced rTMS-induced cortical excitability relative to placebo. This facilitation was specifically blocked by combining DCS with DXM. LZP administration resulted in a significant reduction of MEP amplitudes after rTMS. Results suggest that 10-Hz rTMS-induced plasticity works primarily through NMDAR dependent modulation with LTP-like mechanisms as opposed to GABAergic reduction. Our pilot study is the first to compare NMDAR v. GABAR in rTMS-induced plasticity and found the safety and feasibility of a 4-arm crossover protocol with each drug combined with the full 3000 pulse 10-Hz rTMS protocol. Our results may guide future clinical translation leveraging mechanistic understanding to improve therapeutic efficacy.
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BibTeX
@article{kweon2026exploration,
title = {{Exploration of NMDA and GABA receptor-mediated plasticity induced by 10-Hz repetitive transcranial magnetic stimulation}},
author = {Jamie Kweon and Hakjoo Kim and Prem Ganesh and Megan M. Vigne and Andrew M. Fukuda and Boyu Ren and Linda L. Carpenter and Joshua C. Brown},
journal = {Translational Psychiatry},
year = {2026},
month = jun,
doi = {10.1038/s41398-026-04159-3},
url = {https://doi.org/10.1038/s41398-026-04159-3},
note = {CC BY},
}
RIS
TY - JOUR
TI - Exploration of NMDA and GABA receptor-mediated plasticity induced by 10-Hz repetitive transcranial magnetic stimulation
AU - Jamie Kweon
AU - Hakjoo Kim
AU - Prem Ganesh
AU - Megan M. Vigne
AU - Andrew M. Fukuda
AU - Boyu Ren
AU - Linda L. Carpenter
AU - Joshua C. Brown
PY - 2026
DA - 2026/06/17
JO - Translational Psychiatry
DO - 10.1038/s41398-026-04159-3
UR - https://doi.org/10.1038/s41398-026-04159-3
AB - Although 10-Hz repetitive transcranial magnetic stimulation (rTMS) is an FDA-approved treatment for depression, we do not understand the mechanisms through which rTMS induces therapeutic change. Two competing theories suggest that 10-Hz rTMS induces N-methyl-D-aspartate receptor (NMDAR)-dependent long-term potentiation (LTP), and/or removal of inhibitory gamma-aminobutyric acid receptors (GABARs). We examined these two proposed mechanisms of action in the human motor cortex in a double-blind, randomized, four-arm crossover study in six healthy subjects. We tested plasticity with motor-evoked potentials (MEPs) and learning with serial reaction time task (SRTT) before and after 10-Hz rTMS in the presence of four drugs separated by 1 week each: placebo, d-cycloserine (DCS 100 mg), DCS 100 mg + NMDAR partial antagonist dextromethorphan (DXM 150 mg), and lorazepam (LZP 2.5 mg). NMDAR agonism by DCS enhanced rTMS-induced cortical excitability relative to placebo. This facilitation was specifically blocked by combining DCS with DXM. LZP administration resulted in a significant reduction of MEP amplitudes after rTMS. Results suggest that 10-Hz rTMS-induced plasticity works primarily through NMDAR dependent modulation with LTP-like mechanisms as opposed to GABAergic reduction. Our pilot study is the first to compare NMDAR v. GABAR in rTMS-induced plasticity and found the safety and feasibility of a 4-arm crossover protocol with each drug combined with the full 3000 pulse 10-Hz rTMS protocol. Our results may guide future clinical translation leveraging mechanistic understanding to improve therapeutic efficacy.
SN - 2158-3188
ER -