Title: Dose-dependent response of prefrontal transcranial direct current stimulation on heart rate variability: an electric field modeling study
Laís B. Razza¹ ²*; Stefanie De Smet¹ ²; Stevan Nikolin³; Xander Cornelis²; Matias M. Pulopulos⁴; Rudi De Raedt⁴; Andre R. Brunoni ⁵ ⁶ ⁷; Marie-Anne Vanderhasselt¹ ²
1.Department of Head and Skin, Psychiatry and Medical Psychology, Ghent University Hospital, Ghent University, 9000 Ghent, Belgium. 2.Ghent Experimental Psychiatry (GHEP) Lab, Ghent University, 9000 Ghent, Belgium. 3. School of Psychiatry, University of New South Wales, Sydney, Australia; Black Dog Institute, Sydney, Australia. 4.Department of Experimental Clinical and Health Psychology, Ghent University, Ghent, Belgium. 5. Departamento de Clínica Médica, Faculdade de Medicina da Universidade de São Paulo & Hospital Universitário, Universidade de São Paulo, Av. Prof Lineu Prestes 2565, 05508-000, São Paulo, Brazil. 6. Hospital Universitário, Universidade de São Paulo, São Paulo, Brazil. 7. Serviço Interdisciplinar de Neuromodulação, Laboratório de Neurociências (LIM-27), Departamento e Instituto de Psiquiatria, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
*Correspondence: Laís Boralli Razza, PhD, Department of Head and Skin - Psychiatry and Medical Psychology, Ghent University Hospital, Corneel Heymanslaan 10 – 9000, Ghent,Belgium.
E-mail address:lais.razza@ugent.be.
Abstract
Transcranial direct current stimulation (tDCS) of the prefrontal cortex (PFC) modulates the autonomic nervous system by activating deeper brain areas via top-down pathway. However, effects on the nervous system are heterogeneous and may depend on the amount of current that penetrates the brain due to individual brain anatomical differences. Therefore, we aimed to investigate the variable effects of tDCS on heart rate variability (HRV), a measure of the functional state of the autonomic nervous system. Using three prefrontal tDCS protocols (1.5mA, 3mA and sham), we associated the simulated individual electric field (E-field) magnitude in brain regions of interest with the HRV effects. This was a randomized, double-blinded, sham-controlled and within-subject trial, in which participants received tDCS sessions separated by two weeks. The brain regions of interest were the dorsolateral PFC (DLPFC), anterior cingulate cortex, insula and amygdala. Overall, 37 participants (mean age = 24.3 years, standard deviation = 4.8) were investigated, corresponding to a total of 111 tDCS sessions. The findings suggested that HRV, measured by Root Mean Squared of Successive Differences (RMSSD) and high-frequency HRV (HF-HRV), were significantly increased by the 3.0mA tDCS when compared to sham and 1.5mA. No difference was found between sham and 1.5mA. E-field analysis showed that all brain regions of interest were associated with the HRV outcomes. However, this significance was associated with the protocol intensity, rather than inter-individual anatomical variability. To conclude, our results suggest a dose-dependent effect of tDCS for HRV. Therefore, further research is warranted to investigate the optimal current dose to modulate HRV.
Keywords: transcranial direct current stimulation; heart rate variability; autonomic nervous system; electric field; dose-dependency
Background
Dysregulation in the autonomic nervous system is common in a variety of psychiatric disorders. Heart rate variability (HRV), an index of beat-to-beat variation in the heart, is frequently used to evaluate autonomic (dys)function, and, as such, changes in this measurement are confirmed to be associated with psychiatric illnesses, including depression (Koch et al., 2019)(Borrione et al., 2018).
According to the central autonomic network model, the prefrontal cortex (PFC) and deeper brain regions are involved in high-order autonomic control (Benarroch, 1993). Neuromodulation of the PFC can activate the parasympathetic branch of the autonomic nervous system via top-down influences. This subsequently alters cardiovascular autonomic responses, including HRV (Shaffer et al., 2014)(Thomas et al., 2019). In this sense, previous studies showed that the manipulation of PFC activity using non-invasive brain stimulation (NIBS) techniques can modulate HRV, confirming the prediction of the brain-body connection of central autonomic network theory in humans(Vanderhasselt & Ottaviani, 2022)(Nikolin et al., 2017; Schmaußer et al., 2022).
A NIBS intervention that is particularly promising, due to its safety profile and accessible use, is transcranial direct current stimulation (tDCS). TDCS is able to modulate brain activity via a low-intensity direct electric current applied to the scalp (Lefaucheur & Wendling, 2019). The electric current can increase or decrease cortical excitability in both locally stimulated regions and downstream connected brain networks (Makovac et al., 2017). Although the technique might be able to modulate HRV of healthy and depressive patients by means of targeting the PFC network, the overall findings are still heterogeneous (Razza, Wischnewski, et al., 2023; Wischnewski et al., 2021). This heterogeneity can be explained in part by interindividual differences in brain morphology, which might alter electric current distributions in the brain (Polanía et al., 2018). Hence, it is plausible that variance in the electric current that penetrates specific brain areas due to individual anatomical variability may underlie the subsequent variance observed in the measured HRV response. Recently, technological developments allow evaluating simulations of the electrical current injected into the brain (Saturnino et al., 2019). While some studies have shown that the simulated electric field (E-field) strength might be associated with cognitive and affective prefrontal tDCS effects(Caulfield et al., 2022; Suen et al., 2020), no study so far has investigated its impact on HRV.
In this study the modulatory effects of distinct prefrontal tDCS intensities (1.5mA, 3mA and sham) on the parasympathetic effects (HRV) is investigated in healthy individuals, and it is explored whether the magnitude of the E-field in brain regions of interest is associated with this outcome. Based on the central autonomic network model, the brain regions of interest were the anterior cingulate cortex (ACC), insula, amygdala and the PFC - focusing on the dorsolateral region. We hypothesize that 1) greater current intensities (1.5mA vs 3.0mA) will increase HRV at a population level (reflecting increased parasympathetic control); 2) individual E-field magnitudes in brain regions of interest will explain inter-individual heterogeneity in HRV modulation, with individuals experiencing relatively higher E-fields demonstrating greater HRV modulation (Wei et al., 2018).