{"doi":"10.1016/j.brs.2025.07.004","title":"Trigeminal nerve stimulation as an active control condition in TMS clinical trials: Evidence from heart-brain coupling and clinical outcomes","abstract":"The inertness of sham controls in transcranial magnetic stimulation (TMS) studies, particularly those involving Transcutaneous Electrical Nerve Stimulation (TENS), remains controversial. Using heart-brain coupling (HBC) as a frontal-vagal engagement measure, we analyzed pilot data and data from two placebo-controlled accelerated intermittent theta burst stimulation (aiTBS) trials (combined N = 100). Active-TMS induced significantly stronger HBC compared to sham in both studies, with the effect size for TENS-sham considerably attenuated, and significantly stronger HBC for TENS-sham relative to SAINT-sham (d = 0.9). HBC in the TENS-sham group was associated with clinical improvement (d = 1.12), reflecting antidepressant effects of trigeminal nerve stimulation. These findings suggest TENS-sham should be seen as an active control condition, also controlling for trigeminal nerve stimulation, resulting in downstream vagal and cortical engagement and thus controlling for this non-specific effect of TMS. Future studies should be aware of this active effect and conduct power-analyses accordingly, modifying the expected effect size. Furthermore, HBC could be used to titrate the intensity of TENS-stimulation to minimize active effects.","journal":"Brain stimulation","year":2025,"id":523865,"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":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9474,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":95860,"name":"Nolan Williams","orcid":"0000-0003-4368-3203","position":1,"is_corresponding":false},{"id":230804,"name":"Jonathan Downar","orcid":"0000-0002-5140-174X","position":2,"is_corresponding":false},{"id":1330764,"name":"Aleksandra Dojnov","orcid":null,"position":3,"is_corresponding":false},{"id":1397324,"name":"J. M. Coetzee","orcid":null,"position":4,"is_corresponding":false},{"id":237648,"name":"Roberto Goya‐Maldonado","orcid":"0000-0002-7368-1332","position":5,"is_corresponding":false},{"id":241402,"name":"Martijn Arns","orcid":"0000-0002-0610-7613","position":0,"is_corresponding":true}],"reference_count":12,"raw_metadata":null,"created_at":"2026-07-19T02:50:07.396155Z","pmid":"40651660","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":[]}