Discussion
This study aimed to investigate the modulatory effects of distinct prefrontal tDCS intensities (1.5mA, 3mA and sham) on HRV and explored whether the magnitude of the E-field in brain regions of interest was associated with this outcome. Our hypotheses posited that higher electric currents would lead to increased HRV, while individual anatomical variability would also play a significant role in this modulation. Specifically, we expected that individuals with higher magnitudes of E–fields in brain regions of interest would exhibit greater increases in HRV, as measured by RMSSD and HF-HRV. As hypothesized, the results showed that tDCS was able to modulate both cardiovascular measures via a top-down route. However, only the highest electric intensity (of 3.0mA) increased HRV compared to sham and 1.5mA current. According to our findings, this modulation was not associated with anatomical individual differences per se, as evaluated by computational modeling analysis.
Although this study did not provide evidence to support our hypothesis that inter-individual variability contributes to the heterogeneous effects of tDCS, the results presented here are aligned with the dose-dependent effects of tDCS - with higher electric current intensities producing increased RMSSD and HF-HRV (Goldsworthy & Hordacre, 2017). In this context, a recent meta-analysis showed that the effects of prefrontal tDCS might be only small to moderate for both RMSSD and HF-HRV measures of healthy subjects (Schmaußer et al., 2022). However, it is important to note that a limitation of the aforementioned study was that potential moderators of response to tDCS were not investigated, including tDCS protocols. Therefore, our findings suggest, for the first time, that the variability of tDCS effects on cardiovascular measures might be associated with the heterogeneity of tDCS protocol (as different electric current is applied across published studies, i.e: 1mA, 1.5mA and 2mA), rather than inter-individual anatomical variability.
Following the central autonomic network model, the brain-body connection is important for regulating parasympathetic control and autonomic balance (Cameron, 2009). This occurs when the modulation of cortical and subcortical brain regions - such as the ones discussed here - has the potential to activate parts of the autonomic nervous system that can regulate oscillations of the heart rate (Mulcahy et al., 2019). Hence, it’s important to ensure that this top-down approach (from PFC, to subcortical areas to autonomic nervous system) using tDCS and other non-invasive brain stimulation interventions seems effective. As tDCS delivers a low electric current into the brain and almost 75% of this current is deflected by different layers including skin, bone, hair and cerebrospinal fluid, only a small percentage of the current is indeed able to reach cortical tissue (Vöröslakos et al., 2018). In this sense, we believe that higher currents (i.e: 3mA), compared to lower currents (i.e: 1.5mA) are better able to penetrate into the (sub-) cortical regions, and thereby efficiently modulate the PFC as well as the parasympathetic system via a top-down regulation.
Moreover, it is worth mentioning that the present study employed a neuronavigation method aiming to accurately target the MNI coordinate in the DLPFC optimally associated with the subgenual ACC in depressed patients, using transcranial magnetic stimulation (Fox et al., 2012). Although the tDCS electrodes are larger (5x5cm), the utilization of this precise targeting approach might have increased the connection between PFC and subcortical areas. This is important to note, as previous studies used target location based on the 10-20 EEG system or Beam-F3, both of which are valid methods in the field, but are less accurate than neuronavigation. Therefore, this approach should be suggested for future researchers evaluating tDCS on HRV of depressed patients.
Although our study did not reveal significant inter-individual differences, the analysis utilizing E-field modeling yielded two important findings. Firstly, all the brain regions of interest exhibited associations with the outcome measure, indicating that greater simulated electric current in these areas was associated with more effective manipulation of HRV. This finding further supports the notion that when prefrontal tDCS is applied to healthy individuals, it impacts and modulates all regions that are correlated with the central autonomic network. Secondly, the graphical representation of the E-field results indicates that the administration of a higher current intensity (3.0mA) is associated with increased variability in the E-field within the brain regions of interest. This observation suggests a greater potential for modulatory effects and room for improvement when higher currents are applied.
Both ours and Nikolin and colleagues (Nikolin et al., 2017) studies showed overall increased HF-HRV for active tDCS conditions relative to sham. Overall, the results of the 1.5mA protocol of our study seems really close to what they presented using a current of 2mA. This comparison also supports our hypothesis of a dose-dependent relationship. Finally, our study did not demonstrate a reduction in HRV measures during the concurrent cognitive task when combined with tDCS, as seen by Nikolin and colleagues (Nikolin et al., 2017) . In fact, the graphical representations visually depicted an increase in parasympathetic effects during the 0-back performance, although this finding did not reach statistical significance. It is important to note that while HRV measures typically decrease in stressful situations, the individuals in our study were exposed to an attentional task that engaged PFC activity, which is known to increase HRV. Thus, the engagement of PFC activity during the attentional task may have contributed to the observed increase in HRV, despite the absence of statistical significance.