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).