Trigeminal nerve stimulation as an active control condition in TMS clinical trials: Evidence from heart-brain coupling and clinical outcomes
Bibliographic record
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.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.014 | 0.151 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".