Time Course of Corticospinal Excitability and Autonomic Function Interplay during and Following Monopolar tDCS

While polarity-specific after-effects of monopolar transcranial direct current stimulation (tDCS) on corticospinal excitability are well-documented, modulation of vital parameters due to current spread through the brainstem is still a matter of debate, raising potential concerns about its use through the general public, as well as for neurorehabilitation purposes. We monitored online and after-effects of monopolar tDCS (primary motor cortex) in 10 healthy subjects by adopting a neuronavigated transcranial magnetic stimulation (TMS)/tDCS combined protocol. Motor evoked potentials (MEPs) together with vital parameters [e.g., blood pressure, heart-rate variability (HRV), and sympathovagal balance] were recorded and monitored before, during, and after anodal, cathodal, or sham tDCS. Ten MEPs, every 2.5-min time windows, were recorded from the right first dorsal interosseous (FDI), while 5-min epochs were used to record vital parameters. The protocol included 15 min of pre-tDCS and of online tDCS (anodal, cathodal, or sham). After-effects were recorded for 30 min. We showed a polarity-independent stabilization of cortical excitability level, a polarity-specific after-effect for cathodal and anodal stimulation, and an absence of persistent excitability changes during online stimulation. No significant effects on vital parameters emerged both during and after tDCS, while a linear increase in systolic/diastolic blood pressure and HRV was observed during each tDCS condition, as a possible unspecific response to experimental demands. Taken together, current findings provide new insights on the safety of monopolar tDCS, promoting its application both in research and clinical settings. Introduction Non-invasive brain stimulation (NIBS) techniques are increasingly used as potential treatments for numerous neurological and psychiatric conditions (1–5). The rationale behind the therapeutic use of such techniques is that both repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) may produce changes in the cortical excitability of the stimulated neural networks, outlasting the stimulation period. While rTMS mainly induces long-lasting changes in synaptic efficacy (6), tDCS changes cortical excitability in a polarity-specific manner by modifying the intracellular ion concentrations in the cortical tissue, through an action at the level of the membrane potential: cathodal tDCS (C-tDCS) induces inhibition of the stimulated network, while anodal stimulation (A-tDCS) acts in an opposite way (1–4, 7, 8). Additional action mechanisms of tDCS such as changes in synaptic strength (9) or changes in the resting activity of glial cells (10) have been also documented. tDCS-induced changes in cortical excitability may have positive behavioral consequences, if the dysfunction of the NIBS-conditioned network is associated with the generation/maintenance of a given symptom. Besides having an important role in investigating the physiology of motor (7, 11–14) and visual areas (15–17), where changes of cortical excitability can be directly indexed by neurophysiological parameters, tDCS research has also shown to have a strong translational power, with promising scenarios concerning new treatment options for neurological and psychiatric disorders. Moreover, tDCS devices are freely available on the web market for unsupervised home usage as neuroenhancers (18), opening a worrisome scenario by a medical and social perspective (18, 19). Specifically, tDCS can be delivered by adopting bipolar (4, 7) or monopolar (20, 21) montages: the former implies an “active” (either cathode or anode) and a “reference” electrode placed on the scalp surface, while the latter uses a “reference” placed on an extracephalic target (shoulder, leg, arm, etc.). In this case, the induced electric field may flow toward brainstem structures, thereby potentially affecting the function of the neural centers, which regulate autonomic nervous system functions (22). However, the effects of tDCS techniques on vital parameters as blood pressure, heart-rate variability (HRV), sympathetic/parasympathetic balance, and respiration frequency, are still controversial (23). While a potential modulation of sympathetic activity via the stimulation of motor cortex (24), dorsolateral prefrontal cortex (DLPFC) (25), as well parietal (26), occipital (27), and temporal (28) lobes have been already demonstrated, the variability in terms of electrode montages, study design (cross-sectional vs. parallel), blinding, and tDCS modality applied across studies posit the need for further investigations (19). Furthermore, whether tDCS exerts its effect over the autonomic system mostly during or right after its delivery is still a matter of debate (29), as well as the reliability of tridimensional head models of local current field as vehicle to investigate the aforementioned issues (5). Finally, it is noteworthy that the identification of potential effect of tDCS over CNS structures that govern autonomic nervous function may candidate several pathological conditions as potential targets for treatments, like arterial hypertension (30), vasovagal syncope (31), obesity (29), diabetes (32), and migraine (33), while holding a drawback in terms of its application in neurological and psychiatric population in which such secondary effects could represent a limit instead. Therefore, to originally investigate the online and after-effects of monopolar tDCS on autonomic functions, we simultaneously acquired corticospinal excitability levels and vital parameter data before, during, and after tDCS using a combined TMS–tDCS set-up. Differently from previous investigations available to date, this approach allowed us to originally investigate the effect of tDCS on vital parameters in light of a net measure of its effect on cortical excitability. By monitoring such dynamics through the entire experiment, we will be able to describe the possible modulation of vital parameters as a response to the fluctuations in cortical excitability induced by tDCS. Materials and Methods Participants Ten tDCS-naïve and fully right-handed healthy volunteers with normal neurological examinations took part in the study (five female; mean age 26 ± 3 years). The experiment was performed with the approval of the Ethical Committee of Siena University. An informed consent was obtained from all subjects according to the Declaration of Helsinki. Following a cross-over design, all participants blindly underwent three separate sessions of randomized A-tDCS, C-tDCS, and sham tDCS (S-tDCS) of the dominant primary motor cortex (left M1), each spaced about 1 week apart (5–7 days). They sat comfortably in a reclining chair with their arm fully relaxed in a natural position and their hands pronated on a pillow. Electrophysiological and Vital Parameter Recordings Each recording session started with the identification of the left M1 by searching for the hotspot of the contralateral first dorsal interosseous (FDI) muscle, according to standard single-pulse focal coil TMS session parameters (34). The active tDCS electrode was then applied to the left M1. Then, electrodes for the cardiovascular parameters recordings were applied (35). The TMS hotspot was checked again in order to ensure a stable set-up immediately before the experiment began. The whole time course of the experiment is displayed in Figure 1. In order to guarantee the gold-standard set-up for minimization of trial-to-trial variability of cortical excitability, we used a TMS neuronavigation system throughout the entire experiment, which is per se an original approach into the investigation of tDCS-induced changes in cortical excitability.