{"doi":"10.1016/j.brs.2021.03.016","title":"NMDA-receptor agonist reveals LTP-like properties of 10-Hz rTMS in the human motor cortex","abstract":"Repetitive Transcranial Magnetic Stimulation (rTMS) is a safe and effective treatment for a growing number of neuropsychiatric disorders. While the utilization of clinical rTMS is advancing rapidly, it is happening without a clear mechanistic understanding of how TMS changes the brain. Improved mechanistic understanding could ultimately improve clinical treatments through targeted navigation of the infinite rTMS parameter space and potential pharmacological augmentation. The early hypothesis that high-frequency (≥5-Hz) rTMS works through long-term potentiation (LTP) at the cellular level was based on limited evidence, and competing hypotheses are gaining attention. However, LTP-like effects have been observed with 10-Hz magnetic stimulation in mouse hippocampal slices, including increased dendritic spine size, increased GluA1-receptor composition, and n-methyl-d-aspartate (NMDA)-receptor-dependent potentiation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-receptor-mediated post-synaptic currents [[1]Vlachos A. Muller-Dahlhaus F. Rosskopp J. Lenz M. Ziemann U. Deller T. Repetitive magnetic stimulation induces functional and structural plasticity of excitatory postsynapses in mouse organotypic hippocampal slice cultures.J Neurosci. 2012; 32: 17514-17523Crossref PubMed Scopus (115) Google Scholar]. In the human motor cortex, various plasticity-promoting rTMS protocols depend on NMDA-receptors [2Huang Y.Z. Chen R.S. Rothwell J.C. Wen H.Y. The after-effect of human theta burst stimulation is NMDA receptor dependent.Clin Neurophysiol. 2007; 118: 1028-1032Crossref PubMed Scopus (361) Google Scholar, 3Suppa A. Biasiotta A. Belvisi D. Marsili L. La Cesa S. Truini A. Cruccu G. Berardelli A. Heat-evoked experimental pain induces long-term potentiation-like plasticity in human primary motor cortex.Cerebr Cortex. 2013; 23: 1942-1951Crossref PubMed Scopus (36) Google Scholar, 4Stefan K. Kunesch E. Benecke R. Cohen L.G. Classen J. Mechanisms of enhancement of human motor cortex excitability induced by interventional paired associative stimulation.J Physiol. 2002; 543: 699-708Crossref PubMed Scopus (482) Google Scholar]. However, specificity is lacking, as it is unclear if NMDA receptor activation is sufficient to enhance rTMS-induced facilitation. For example, NMDA-receptor activation with d-cycloserine (DCS) was insufficient to enhance facilitation induced by intermittent theta burst stimulation (iTBS) in two independent studies [[5]Teo J.T.H. Swayne O.B. Rothwell J.C. Further evidence for NMDA-dependence of the after-effects of human theta burst stimulation.Clin Neurophysiol. 2007; 118Crossref Scopus (72) Google Scholar,[6]Selby B. MacMaster F.P. Kirton A. McGirr A. D-Cycloserine blunts motor cortex facilitation after intermittent theta burst transcranial magnetic stimulation a double-blind randomized placebo-controlled crossover study.Brain Stimul. 2019; 12 (2019): 1063-1065Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar]. By contrast, DCS was sufficient to enhance 10-Hz rTMS-mediated facilitation over 1-hour in a crossover design, again supporting an LTP-like mechanistic hypothesis [[7]Brown J.C. DeVries W.H. Korte J.E. Sahlem G.L. Bonilha L. Short E.B. et al.NMDA receptor partial agonist, d-cycloserine, enhances 10 Hz rTMS-induced motor plasticity, suggesting long-term potentiation (LTP) as underlying mechanism.Brain Stimul. 2020; 13: 530-532Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar]. Combining pharmacology and rTMS with mechanism-revealing neurophysiology protocols is an unexplored approach. Paired-pulse protocols including intracortical inhibition and intracortical facilitation (ICI and ICF) are well-established. They capitalize on differential stimulation intensity sensitivities of GABAergic and glutamatergic neurons, respectively [[8]Ziemann U. Rothwell J.C. Ridding M.C. Interaction between intracortical inhibition and facilitation in human motor cortex.J Physiol. 1996; 496:","journal":"Brain stimulation","year":2021,"id":159600,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":40,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9606,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":670820,"name":"Shiwen Yuan","orcid":"0000-0003-1477-6064","position":1,"is_corresponding":false},{"id":290601,"name":"William H. 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