Discussion
depression, treatment-resistant depression, pain
To the best of our knowledge, this is so far the largest study investigating the effect on HRV after a treatment course of iTBS targeting the DMPFC in depression. We did not detect any significant effects on the HRV metrics. Neither there were any correlations between change in HRV and symptom change detected, nor there was any predictive value of baseline HRV on symptom change.First, it has to be pointed out that we specifically assessed HRV before and after the iTBS treatment course and therefore cannot draw any conclusions about whether iTBS has an acute and transient effect on HRV. Comparisons with studies on healthy individuals are hindered due to the fact that no healthy individuals receive longer treatment courses. Of the sham-controlled studies on healthy individuals, there have been no effects that lasted over time (As for non-sham-controlled studies of the effect of rTMS on HRV, an open study found increased SDNN between baseline and follow-up 2 weeks later in 30 patients with depression treated with rTMS (targeting DLPFC using 5-cm-rule, 15 Hz, 100% of resting motor threshold (rMT), 1,500 pulses per session). They assessed HRV before and after the treatment, which possibly eliminates the potential confounding effects of the simultaneous pain or sensational stimuli of rTMS. However, since the study was not sham-controlled, there can be no speculations of the specific effects of rTMS on HRV (Regarding the correlation between HRV change and symptom change, we did not find any such correlations. In the literature, this question has been of interest as a way of approaching the causal interactions between HRV and symptom change. In an open study of 27 patients receiving rTMS, there was no correlation between symptom reduction and HRV or other autonomic parameters (We could not find any predictive value of HRV regarding treatment response. Here, we analyzed all open treatment sessions in our study (There are some limitations of our study. Even though our sample is, to our knowledge, the so far largest sample investigating the effects of a sham controlled treatment course of iTBS on HRV, it is still a small sample size. It has been argued that interpreting CIs is better than post-hoc analyses to judge the robustness of ‘null’ results (Regarding the HRV data extraction, we could not ascertain that the participants actually slept. However, the time frame of midnight to 5 am is a time when most people do sleep, and the participants in both groups reported a sleeping time of around 7 h. Furthermore, the mean starting time for the HRV data did not differ between the groups. The baseline and the follow-up HRV data were in some cases extracted from different times during the night, but the mean difference was only 25 min in the whole sample (see We chose SDNN as our primary outcome. Our main interest has not been the parasympathetic nervous system in isolation, and SDNN originates from both sympathetic and parasympathetic signaling (Some argue that baseline statistical comparisons between the groups in randomized data are not necessary (The participants’ medications were quite diverse, possibly reflecting the heterogeneity of the treatment-resistant depression concept and the aim of recruiting a clinically representative sample. Importantly, all drug regimens were kept stable during this study, and even though these medications could have an impact on HRV, it is therefore unlikely that they would contribute to a change in HRV during the study period. Some drugs prescribed (most notably TCAs) could cause a high occupancy of the muscarinic receptors in the heart and might thereby diminish the vagal possibilities to modulate heart rate, thus rendering these participants unable to change their HRV. There were however no substantial differences in TCA prescription between the active and the sham groups.Eight participants’ symptom ratings originated from 4 weeks after baseline rather than 2 weeks after baseline. However, at least some of the symptoms assessed are not subject to rapid fluctuations but rather quite stable. Furthermore, excluding these participants did not materially change the results (data not shown).The use of delta values in correlational analyses may introduce measurement error from both baseline and follow-up assessments with subsequent unreliability. Our results from these analyses are therefore to be interpreted with caution, and the reader is referred to Our sample consisted of patients recruited to a transdiagnostic study of the effects of iTBS on negative symptoms. The results are therefore not necessarily generalizable to a wider group of patients with depression. The patients who come in contact with rTMS are however often labeled as ‘treatment resistant’, and even if these patients can be defined in many ways (We conclude that treatment with dorsomedial iTBS did not increase HRV, but it did not have any negative effects on the cardiac autonomic nervous system.