2026 ECNP Congress

PS03-3189

Frontoparietal network-optimised versus standard targeting for bilateral theta-burst stimulation in depression: a naturalistic randomised study protocol

Joshua Tritsch — J. Marx, A. Völkel, M. Poli, A. Hasan, W. Strube · University Augsburg, Psychiatry and Psychotherapy, Augsburg, Germany

2026 ECNP Congress

Introduction

Repetitive transcranial magnetic stimulation (rTMS) is an established treatment for major depressive disorder (MDD), yet response rates remain variable. Stimulation site selection is a key contributor to this variability. The Beam F3 method, the most widely used scalp-based heuristic, targets the dorsolateral prefrontal cortex (DLPFC) but engages multiple functional networks non-selectively across individuals [1]. The recently proposed F5-AF7 method optimises coil placement to more selectively stimulate the frontoparietal network (FPN), which may be linked to the development and alleviation of depression [2]. However, this approach has not been tested prospectively in a clinical treatment setting. Separately, neuro-cardiac-guided TMS research demonstrates that DLPFC stimulation modulates heart rate (HR) and heart rate variability (HRV) in a target- and intensity-specific manner via the frontal-vagal pathway [3,4], suggesting these parameters may index differential network engagement.

Aims

This study aims to (1) compare clinical response and remission rates between F5-AF7 and Beam F3 targeting in bilateral theta-burst stimulation (TBS) for MDD, and (2) evaluate whether cardiac autonomic responses during intermittent TBS (iTBS) differ between targeting methods and predict treatment outcome.

Methods

In this naturalistic, two-armed study, patients with MDD (target N=200) receiving bilateral TBS as part of routine clinical care are randomly allocated to one of two targeting conditions: (1) Beam F3 with coil handle oriented 45° to the sagittal midline, or (2) F5-AF7 with coil handle oriented along the F5-AF7 axis [2]. Left-sided iTBS is mirrored to the right hemisphere for continuous TBS (cTBS), using the corresponding targeting method (Beam F4 or F6-AF8, respectively). Both arms receive 600 iTBS pulses (left) and 600 cTBS pulses (right) daily over six weeks, followed by four maintenance sessions. Primary outcomes are response (≥50% reduction) and remission (≤10 points) on the Montgomery-Åsberg Depression Rating Scale (MADRS), with the Beck Depression Inventory-II (BDI-II) as a secondary clinical measure. Further secondary outcomes include cardiac autonomic measures: (1) heart-brain coupling (HBC) power, computed as spectral power at the iTBS entrainment frequency (0.1 Hz, derived from the 2s-on/8s-off cycle) in the R-R interval time series, adapting the NCG-TMS framework [3,4] to iTBS temporal structure, (2) mean HR change during iTBS-stimulation blocks and (3) change from baseline in resting HRV, calculated as root mean square of successive differences (RMSSD). HBC analysis applies to the left-sided iTBS component only, as cTBS lacks the on-off cycling required for cardiac entrainment. Group differences in clinical outcomes will be analysed using logistic regression. Correlations between cardiac measures and clinical outcome will be examined as exploratory analyses.

Expected results

We hypothesise that F5-AF7 targeting, through more selective FPN engagement, yields superior response and remission rates and produces stronger cardiac autonomic modulation compared to Beam F3. Interim data from approximately 80 patients are expected by October 2026.

Conclusions

This study provides the first prospective clinical comparison of FPN-optimised (F5-AF7) versus standard (Beam F3) targeting for bilateral TBS in MDD. Integrating online cardiac monitoring during treatment may identify physiological markers of target engagement predictive of clinical response, bridging network-informed targeting and neuro-cardiac-guided stimulation.

References

  1. Fox, M.D., Buckner, R.L., White, M.P., Greicius, M.D., Pascual-Leone, A., 2012. Efficacy of transcranial magnetic stimulation targets for depression is related to intrinsic functional connectivity with the subgenual cingulate. Biol. Psychiatry 72(7), 595-603.
  2. Lueckel, M., Kachel, K., Engelmann, J., Bergmann, T.O., Müller-Dahlhaus, F., 2026. A standard coil placement for reliable transcranial magnetic stimulation of the frontoparietal depression network: the ‘F5-AF7 method’. medRxiv doi:10.64898/2026.01.25.26344778.
  3. Feng, Z.J., Martin, S., Numssen, O., Weise, K., Jing, Y., Gerardos, G., et al., 2026. Target-specificity and repeatability in neuro-cardiac-guided TMS for heart-brain coupling. Transl. Psychiatry 16, 79.
  4. Dijkstra, E., van Dijk, H., Vila-Rodriguez, F., Zwienenberg, L., Rouwhorst, R., Coetzee, J.P., et al., 2023. Transcranial magnetic stimulation-induced heart-brain coupling: implications for site selection and frontal thresholding. Biol. Psychiatry Glob. Open Sci. 3(4), 939-947.