{"doi":"10.1016/j.brs.2020.01.005","title":"NMDA receptor partial agonist, d-cycloserine, enhances 10 Hz rTMS-induced motor plasticity, suggesting long-term potentiation (LTP) as underlying mechanism","abstract":"While daily repetitive transcranial magnetic stimulation (rTMS) is FDA-approved to treat depression and obsessive-compulsive disorder, we are still unclear about its therapeutic mechanism of action. Better understanding of the fundamental mechanisms of rTMS-induced changes would likely refine and improve this therapy. Animal studies suggest that 10 Hz rTMS may work through long-term potentiation (LTP), a form of synaptic plasticity [[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 (140) Google Scholar]. In humans, several studies have demonstrated that n-methyl-d-aspartate (NMDA) receptor activity, a critical step in the LTP pathway, is necessary [[2]Ziemann U. Hallett M. Cohen L.G. Mechanisms of deafferentation-induced plasticity in human motor cortex.J Neurosci. 1998; 18: 7000-7007Crossref PubMed Google Scholar,[3]Huang 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 (415) Google Scholar], but not sufficient [[4]Teo J.T. Swayne O.B. Rothwell J.C. Further evidence for NMDA-dependence of the after-effects of human theta burst stimulation.Clin Neurophysiol. 2007; 118: 1649-1651Crossref PubMed Scopus (84) Google Scholar,[5]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: 1063-1065Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar] for 0.1 Hz rTMS paired with ischemic nerve block (INB)- and theta burst stimulation (TBS)-induced motor plasticity. Surprisingly, there are no pharmacologic studies testing whether 10 Hz rTMS, as used clinically, depends on synaptic plasticity. We hypothesize that 10 Hz rTMS enhances motor excitability through NMDA receptor-dependent LTP of glutamatergic synapses, and that partial agonism of this pathway by d-cycloserine (DCS) is sufficient to further potentiate motor excitability in healthy humans. Consistent with our hypothesis, we observed that participants in this small crossover study appeared to have more cumulative potentiation after 10 Hz rTMS with DCS relative to placebo. We recruited ten healthy adults (6 men, 26–37 years old) into a randomized, double-blind, crossover study approved by the Medical University of South Carolina Institutional Review Board. All participants provided informed consent prior to any research procedures. We included healthy participants without TMS contraindications between the ages of 18 and 50. We randomly assigned participants to begin the crossover study with either 100 mg d-cycloserine (DCS, an NMDA receptor partial agonist) or identical microcrystalline cellulose capsules (Tidewater pharmacy, Mt. Pleasant, SC) in a blinded manner on separate visits. All 10 participants received both medications, half received active drug first. We administered the drug approximately 2 hours before rTMS as done previously [[6]Nitsche M.A. Jaussi W. Liebetanz D. Lang N. Tergau F. Paulus W. Consolidation of human motor cortical neuroplasticity by D-cycloserine.Neuropsychopharmacology. 2004; 29: 1573-1578Crossref PubMed Scopus (281) Google Scholar]. We obtained baseline measurements of motor excitability after drug was administered in order to differentiate whether the drug affected basal excitability (baseline) as opposed to rTMS-induced plasticity (15–60 minutes after rTMS, Fig. 1A). Following baseline measurements, we administered 20 minutes of 10 Hz rTMS. We then remeasured motor excitability at 15 minute increments for 60 minutes. We ensured all TMS and rTMS pulses were given within 2 mm of the target motor “hotspot”","journal":"Brain stimulation","year":2020,"id":58038,"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":74,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9622,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":290601,"name":"William H. DeVries","orcid":null,"position":1,"is_corresponding":false},{"id":304030,"name":"Jeffrey E. Korte","orcid":"0000-0001-7369-9228","position":2,"is_corresponding":false},{"id":304031,"name":"Gregory L. Sahlem","orcid":"0000-0002-7225-3109","position":3,"is_corresponding":false},{"id":241340,"name":"Leonardo Bonilha","orcid":"0000-0002-6153-8942","position":4,"is_corresponding":false},{"id":304032,"name":"E. Baron Short","orcid":"0000-0001-7390-6717","position":5,"is_corresponding":false},{"id":106043,"name":"Mark S. George","orcid":"0000-0003-1767-1815","position":6,"is_corresponding":false},{"id":304029,"name":"Joshua C. Brown","orcid":"0000-0003-0887-2746","position":0,"is_corresponding":true}],"reference_count":7,"raw_metadata":null,"created_at":"2026-07-18T21:07:11.345501Z","pmid":"32289670","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}