Neuro-cardiac guided rTMS as a stratifying method between the '5cm' and 'BeamF3' stimulation clusters Dear editor, Fitzgerald [1] reviewed the question 'Targeting repetitive transcranial magnetic stimulation in depression: do we really know what we are stimulating and how best to do it?'. Two clusters of stimulation targets in use for rTMS treatment in major depressive disorder (MDD) emerge, one surrounding the more posterior '5-cm' rule and another surrounding the more anterior 'Beam-F3' target. Given the fact that large effectiveness studies have demonstrated comparable response (47e58 %) and remission (29e37 %) rates for the 'Beam-F3' cluster [2] and '5-cm' cluster [3] respectively, we hypothesize if these comparable rates could be explained by inter-individual differences. This is in line with Fitzgerald's notion that ' … some patients are just likely to be better off treated at a posterior site and others more anteriorly, due to the connectivity of the networks or individual elements of prefrontal anatomy … '. Thus, effectively addressing such inter-individual differences and 'stratify' patients to either the 'Beam-F3' or '5-cm' cluster could result in increased response and remission rates, whilst at the same time not 'doing any harm' given that both heuristics are already widely implemented and used in clinical practice. In analogy, one could consider this an 'SSRI-vs-SNRI', where we know that group level response and remission rates are the same when patients are randomized, but when stratifying people to one or the other using a biomarker such as EEG alpha asymmetry, this could significantly enhance clinical response on the individual level [4,5].One technique that may be considered is neuro-cardiac guided rTMS (NCG-TMS). This technique aims to activate the frontalvagal pathway, resulting in downstream effects observed as heartrate (HR) decelerations [6,7]. This frontal-vagal network shares overlapping functional nodes with the deregulated brain network associated with MDD, including the DLPFC, sgACC and vagal nerve [7]. Since Fitzgerald's review, Iseger et al. [8] further replicated and validated the NCG-TMS method by stimulating multiple 10-10 EEG sites with 10Hz. The specific HR deceleration at stimulation sites F3/F4 and FC3/FC4, respectively corresponding to the 'Beam-F3' and '5cm' clusters, as well as the acceleration of HR at all other stimulation sites (Fig. 1Ba) was replicated.However, until now the Iseger et al.[8] study as well as prior studies only included healthy participants. Therefore, before considering the NCG-TMS method as a site-stratification method for MDD treatment, it requires replication in an MDD population.Thirty-three MDD patients (average age 52.0, 15 male) who received rTMS for treatment of MDD, underwent an NCG-TMS assessment either at session 10 of treatment, or after unsuccessfully

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<b><i>Introduction:</i></b> Currently, major depressive disorder (MDD) treatment plans are based on trial-and-error, and remission rates remain low. A strategy to replace trial-and-error and increase remission rates could be treatment stratification. We explored the heartbeat-evoked potential (HEP) as a biomarker for treatment stratification to either antidepressant medication or rTMS treatment. <b><i>Methods:</i></b> Two datasets were analyzed: (1) the International Study to Predict Optimized Treatment in Depression (iSPOT-D; <i>n</i> = 1,008 MDD patients, randomized to escitalopram, sertraline, or venlafaxine, and <i>n</i> = 336 healthy controls) and (2) a multi-site, open-label rTMS study (<i>n</i> = 196). The primary outcome measure was remission. Cardiac field artifacts were removed from the baseline EEG using independent component analysis (ICA). The HEP-peak was detected in a bandwidth of 20 ms around 8 ms and 270 ms (N8, N270) after the R-peak of the electrocardiogram signal. Differences between remitters and non-remitters were statistically assessed by repeated-measures ANOVAs for electrodes Fp1, Cz, and Oz. <b><i>Results:</i></b> In the venlafaxine subgroup, remitters showed a lower HEP around the N8 peak than non-remitters on electrode site Cz (<i>p</i> = 0.004; <i>d</i> = 0.497). The rTMS group showed a non-significant difference in the opposite direction (<i>d</i> = −0.051). Retrospective stratification to one of the treatments based on the HEP resulted in enhanced treatment outcome prediction for venlafaxine (+22.98%) and rTMS (+10.66%). <b><i>Conclusion:</i></b> These data suggest that the HEP could be used as a stratification biomarker between venlafaxine and rTMS; however, future out-of-sample replication is warranted.