Background
Upper limb sensorimotor innervation arises mostly from the cervical region of the spinal cord (SC). Several clinical conditions, such as upper limb weakness, sensory deficit or pain, can be associated with cervical spinal circuitry dysfunctions.
Trans-spinal direct current stimulation (tsDCS) has recently emerged as a non-invasive technique with promising neuromodulatory effects on spinal circuitry related to motor and sensory responses of the upper and lower limbs [
7,
8]. tsDCS has a similar approach as transcranial direct current stimulation (tDCS), a non-invasive brain stimulation method for modulating cortical excitability [
28]. It applies a constant low intensity electric current through surface electrodes. However, tsDCS and tDCS differ in their principles of application due to the significant heterogeneity of their target tissues. Whereas anodal tDCS produces facilitation in cortical motor responses [
28], exploratory tsDCS studies in humans report a variety of polarity-dependent effects in spinal motor responses when stimulating the cervical SC: facilitation of motor responses of abductor digiti minimi (ADM) and abductor policis brevis (APB) muscles was observed during cathodal tsDCS applied over C7 spinous process (s.p.), with the anode over the right deltoid (rD) muscle (C7-rD montage, [
4]); increased amplitude of motor evoked potentials (MEP) of the flexor carpi radialis (FCR) was observed independently of the polarity of the electrodes, placed at C7 s.p. and cervicomental angle (C7-CMA montage; [
22]). Cervical tsDCS was also observed to increase corticophrenic pathway excitability, considering a C4-CMA montage: increased diaphragmatic MEP amplitude was observed independently of C4 polarity and tidal volume was increased with the cathode placed at C4 [
25].
tsDCS neuromodulatory effects may result from local variations of the current density and electric field (E-field) along neurons, resulting in specific polarizing effects in the transmembrane potential, with axon terminals identified as the dominant cellular target [
34,
37]. These variations are affected by various stimulation parameters such as electrode placement and geometry, or injected current intensity and polarity, just as in tDCS [
15,
20,
41].
Computational studies using realistic human models based on MRI are essential tools to predict the electrode montages and stimulation parameters that maximize current delivery and E-field distribution in a specific clinical target [
11,
20,
24,
30]. There are few modelling studies published on tsDCS delivery on human lumbar and thoracic SC regions; these studies predict maximum E-field magnitude between the electrodes with a stronger longitudinal component in the spinal canal [
15,
16,
20,
31]. Modelling predictions seem to explain physiological measures obtained during experimental conditions in cervical tsDCS, using MRI-based rat models or simple geometric human models of the cervical SC: diverse electrode montages resulted in different current and E-field distributions, corresponding to different physiological outcomes [
12,
49].
The aim of this study is to present a modelling work considering three electrode montages previously explored in the studies cited above, and a longitudinal montage with two electrodes over the SC, since this is thought to result in less variability in experimental results, compared to anterior-posterior montages, as suggested in Dongés et al. [
13]. Next, we proceed to present the results of an experimental study carried out in healthy human volunteers using this longitudinal electrode montage, to address neuromodulatory effects on motor and sensory pathways of the upper limb.
Discussion
Current density and E-field predictions from the modelling study
Current density and E-field distributions have a higher longitudinal component in the SC. Longitudinal fields were reported in other modelling studies on thoracic and lumbar tsDCS [
15,
16,
20,
31], This longitudinal tendency is due to the cable-like structure of the spine, with a conductive core (spinal cord and CSF) surrounded by an insulating sheath (vertebral column).
All montages present regions with E-field magnitude above 0.15 V/m, which is in line with the observed neuromodulatory effects using C7-rD, C7-CMA and C4-CMA, however these regions are located in different part of the SC (Fig.
3, Table
2), which may account for the differences observed between studies using different montages. Niérat et al. [
25] observed increased excitability of the corticophrenic pathway using C4-CMA montage, which is consistent with a larger E-field magnitude predicted in C3-C5 segments, related with the phrenic nerve (Fig.
3). Bocci et al. [
4] reported improved upper limb motor recruitment and shortening of peripheral silent period (PSP) after cathodal-tsDCS using C7-rD, which is predicted to induce a stronger field in C6-C7 spinal segments, from where part of the brachial plexus arises. Exploratory studies using C7-CMA montage report different effects, such as MEP amplitude increase without changes in H-reflex [
22] or only acute changes in MEP amplitude during combined cathodal-tsDCS and cervicomedullary stimulation [
12]. The length of E-field maximum regions also indicates which montages are suitable for wider (C3-T3, C7-rD) or more focal (CMA montages) stimulation.
Local E-field maxima appear mostly near the WM/GM interface at the dorsal and ventral horns (Fig.
4). Previous numerical modelling studies on invasive spinal cord stimulation found that the EF component parallel to fibres (corresponding to E
long in SC) have an influence on the transmembrane potential of collateral fibres, originating from the spinal-WM columns, as they bent into the spinal-GM [
45]. The same effect was also predicted in transcranial magnetic stimulation (TMS): there may be stimulation of pyramidal tract neurons in the regions where these fibres bend after entering the cortical WM [
40]. The neuromodulatory effects that were observed in the exploratory studies on cervical tsDCS mentioned above may be due to the strong E-field variations along the collateral fibres as they bend and pass the WM/GM interface.
The E-field reaches magnitudes above 0.15 V/m in posterior regions of brainstem and cerebellum in higher cervical electrode montages (C4-CMA, C3-T3), thus neuromodulation of vegetative functions can be considered (Fig.
3). Since these tissues were considered homogeneous, a model with distinct WM and GM will allow more accurate predictions of tsDCS effects.
The inverse relations found between E-field magnitude and CSF volume distributions were also observed in thoracic and lumbar tsDCS studies [
15,
16]. Individual anatomical variability may originate different tsDCS clinical outcomes, thus subject-specific models should be considered to predict the optimal electrode montages.
Neuromodulatory effects of C3-T3 montage
C3-T3 resulted in the highest current density and E-field magnitudes, with maxima at C6-C7 spinal segments, where part of the upper limb innervation arises. Longitudinal bipolar montages (both electrodes over the SC) or monopolar montages (one electrode over the target area and the other at a considerable distance) were recommended by Dongés et al. [
13] for upper limb function neuromodulation, due to the strong longitudinal component induced. We observed neuromodulatory effects on upper limb sensorimotor responses using C3-T3.
Effects on sensory responses
A significant difference was only detected for SEP N9 (F(2, 18) = 6.797,
p = 0.006), however the significance did not resist pairwise comparisons (Fig.
5). Brachial plexus EP/N9 SEP responses are mainly generated by nerve trunk and roots activity close to the SC [
6]. Our model contains nerve exits through vertebral foramina with poor anatomical detail. The E-field distributions presented hotspots near foramina, as seen in animal modelling studies [
42]. Spinal roots may contribute to dorsal root ganglia and peripheral nerve excitation, due to a local current focusing caused by the CSF high conductivity near vertebral foramina, supporting our observation.
Effects on motor responses
MEP latency in ADM decreased significantly by cathodal stimulation compared with sham condition (Fig.
6). This indicates a polarity-dependent facilitation of motor responses with the cathodal condition, probably caused by increased LMN excitability. In addition, we observed a statistically significant decrease in CMCT by cathodal stimulation, with no changes in PCMT. Both findings are in agreement with previous observations, where a cathodal-dependent LMN facilitation is reported (e.g. [
4,
25]). Struijk et al. [
44] predicted that cervical epidural stimulation polarity effects vary with spinal dorsal fibres orientation with respect to the E-field: longitudinal and tangential dorsal fibres depolarize near the cathode and radial fibres near the anode. The high E
long component predicted in C3-T3 may originate the effects observed on MEP latency, not reported previously in other studies. CSP duration was also addressed in the study to observe if there were effects on inhibitory pathways; however, we did not disclose significant differences. In addition, no effect was observed in lower limb MEP responses (Table
3), suggesting that tsDCS neuromodulation may have only a local effect, without evidence of propagated supra or infraspinal levels effect.
M-waves, H-reflex, F-waves and conduction times were assessed in 5 subjects to address possible tsDCS effects on LMN excitability, but the results were not conclusive. We observed a non-significant increase of the H:M ratio mean values after cathodal condition (Table
3), which might indicate a facilitated MN recruitment by Ia stimulation, also consistent with an increased spinal excitability. One limitation is the small number of tested subjects, in the future this should be repeated in a larger population.
Considerations on methodology and future research
The number of tissues included in the model was a trade-off between accuracy in field estimates and high-quality volume meshing, to avoid excessive computation time and memory costs. The artificially designed spinal-GM mask is a low-resolution contour that does not represent an accurate change in size across the cervical enlargement. Even so, it was relevant for a more realistic E-field prediction, due to the different WM and GM electric properties.
Future modelling work should address spinal networks to predict the influence of the E-field in neuronal transmembrane potential and understand the variability of observations. Considering the influence of CSF narrowing predicted by the model, it will be important to determine the influence of inter-subject variability in tsDCS outcomes by comparing E-field predictions in different human models.
One of the main limitations of this study is the sample size formed by young subjects. A larger sample with wider age range would be advisable to confirm our experimental findings reported. Also, recording responses during tsDCS and after tsDCS offset could inform on acute and after effects, as observed previously (e.g. [
1,
12,
13,
26,
27]). Two further limitations of our study is that we have not explored the modulation of corpus callosum by testing ipsilateral CSP and we did not evaluate phrenic nerve responses to test neuromodulation of C3–5 motor nuclei. Future studies should also address neuromodulation of cerebellum and brainstem circuitry using rostral cervical montages, considering the values of the predicted E-field in those regions.
Conclusion
This study presents evidence of neuromodulatory effects on sensorimotor spinal pathways using a new cervical tsDCS montage, informed by a computational study based on a realistic human model. Since anatomical features and electrode position influence current and E-field profiles, future tsDCS experimental studies should be optimized by computational models to design effective tsDCS protocols.
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