Transcutaneous spinal direct current stimulation modulates human corticospinal system excitability

Abstract

transcutaneous spinal direct current stimulation (tsDCS) is a simple, painless, and noninvasive technique for modulating spinal cord function in humans (Cogiamanian et al. 2011, 2012; Lamy and Boakye 2013b; Priori et al. 2014). tsDCS consists in delivering a constant direct current (DC) at 1.5–2.5 mA over the spinal cord through a pair of sponge electrodes. The technique induces effects lasting from minutes to hours (Cogiamanian et al. 2008; Lamy et al. 2012; Lim and Shin 2011; Winkler et al. 2010) and is well tolerated by subjects. After the first reports (Cogiamanian et al. 2008; Winkler et al. 2010), this noninvasive method for spinal neuromodulation has come into increasingly widespread use (Cogiamanian et al. 2011; Hubli et al. 2013; Lamy and Boakye 2013b). Although different settings and stimulation parameters have been used, the “monopolar” montage (active electrode over the lower thoracic spinal cord, return electrode over the right arm) reduces the spread of the current toward the higher spinal cord levels or to the brain stem (Parazzini et al. 2014). Equally important, longitudinal electrical fields, such as those induced by this montage, may have important implications for rehabilitation, as they promote axonal regrowth and prevent fiber degeneration (Hernandez-Labrado et al. 2011).

In earlier research in our laboratory (Cogiamanian et al. 2008), we found that thoracic anodal tsDCS depresses the cervico-medullary somatosensory evoked potential (SEP) component (P30). tsDCS also modulates postactivation H-reflex dynamics (Lamy et al. 2012; Winkler et al. 2010) and the flexion reflex in the human lower limb (Cogiamanian et al. 2011). Further experiments reported that tsDCS impairs conduction in the ascending nociceptive spinal pathways, thus increasing pain tolerance in healthy subjects (Truini et al. 2011). Cervical spinal DC stimulation increased upper limb muscle motor evoked potential (MEP) amplitudes (Lim and Shin 2011). The effects induced by tsDCS could arise from the influence of electric field on impulse conduction, membrane excitability, and γ-aminobutyric acid (GABA)ergic and glutamatergic transmission (Priori et al. 2014). Whatever the mechanisms, by modulating spinal cord function, tsDCS could provide a novel therapeutic tool complementary to drugs and invasive spinal cord stimulation in managing various pathological conditions, including pain, spasticity, and movement disorders.

Having more information on the underlying mechanisms is an essential prerequisite for designing future clinical applications, and, more specifically, to understand whether and how tsDCS influences the corticospinal system would be relevant. Although interesting, the work of Lim and Shin (2011) on upper limb motor responses cannot rule out possible nonspecific effects. Hence, to expand the knowledge about tsDCS effects on the human corticospinal pathways, we tested upper and lower limb MEPs elicited by transcranial magnetic stimulation (TMS) in a group of healthy subjects before and after tsDCS. To evaluate possible motor neuronal or reflex excitability changes induced by tsDCS we also tested the F wave from the lower limb abductor hallucis (AH) and upper limb abductor digiti minimi (ADM) muscles and the H reflex from soleus muscle.

MATERIALS AND METHODS

RESULTS

All participants tolerated the procedure well, and none of them reported adverse effects. Participants occasionally reported a slight tingling or itching sensation below the stimulating electrodes (not distinguishable between the 2 polarities) that disappeared within a few seconds or after wetting the electrode sponges.

tsDCS effects in lower limb muscles.

No differences were found between anodal and cathodal tsDCS in baseline values for any of the measured variables in the lower limb muscles. Neither anodal nor cathodal tsDCS induced changes in H-reflex and F-wave variables (Table 1).

Table 1.

Changes in F-wave and H-reflex variables over time in both experimental conditions (anodal and cathodal stimulation)

	F Wave						H Reflex Soleus
	AH			ADM
	Minimal latency, ms	Mean latency, ms	Dispersion, ms	Minimal latency, ms	Mean latency, ms	Dispersion, ms	Threshold, ms	Latency, ms	Area, mVms	Ratio H/M
Anodal
B	46.4 ± 1.3	48.2 ± 1.5	4.3 ± 0.6	25.8 ± 0.6	27.9 ± 0.8	2.9 ± 0.5	14.7 ± 3.5	28.9 ± 1.0	7.4 ± 1.0	0.4 ± 0.1
T0	47.0 ± 1.5	49.3 ± 1.4	4.3 ± 0.5	26.2 ± 1.0	27.8 ± 0.8	2.8 ± 0.7	13.9 ± 2.8	28.3 ± 1.3	7.1 ± 0.6	0.4 ± 0.05
T30	47.2 ± 1.4	50.5 ± 2.5	4.4 ± 0.7	26.3 ± 0.9	28.3 ± 1.9	3.0 ± 0.4	13.9 ± 1.8	29.3 ± 1.4	7.7 ± 0.9	0.4 ± 0.13
Cathodal
B	46.3 ± 1.2	48.6 ± 1.2	4.4 ± 0.5	25.3 ± 1.2	27.8 ± 1.5	3.0 ± 0.7	14.1 ± 3.0	28.0 ± 1.2	7.7 ± 0.6	0.4 ± 0.04
T0	46.3 ± 1.4	48.8 ± 1.7	4.7 ± 0.3	25.5 ± 1.5	28.0 ± 1.0	3.1 ± 0.4	14.1 ± 2.5	27.8 ± 1.3	7.6 ± 1.1	0.4 ± 0.1
T30	47.2 ± 1.6	49.1 ± 1.5	4.8 ± 0.7	26.0 ± 1.1	28.3 ± 1.0	2.8 ± 0.6	13.8 ± 2.7	28.9 ± 0.8	7.9 ± 1.4	0.3 ± 0.3
P value	0.6	0.2	0.8	0.3	0.9	0.3	0.8	0.7	0.8	0.3

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Data are means ± SE. We found no significant changes in F-wave and H-reflex variables across the different time points [baseline (B), immediately after transcutaneous spinal direct current stimulation (tsDCS) offset (T0), and at 30 min after tsDCS offset (T30)].

AH, abductor hallucis; ADM, abductor digiti minimi; H/M, maximal H reflex/maximal compound muscle action potential.

P values refer to 2-way repeated-measures ANOVA with stimulation and time as factors (interaction effects).

Although MEP latency showed a nonspecific effect of time (2-way ANOVA, factor time: P = 0.009) [baseline latency values were in general shorter than latency values at T30 (post hoc analysis: baseline vs. T30 103.53 ± 0.95%, P = 0.008)], MEP latency was not affected by tsDCS (2-way ANOVA, factor stimulation: P = 0.83) or by the interaction between tsDCS and time (2-way ANOVA, interaction stimulation × time: P = 0.85).

RMT was affected by tsDCS (2-way ANOVA, factor stimulation: P = 0.012, factor time: P = 0.11; interaction stimulation × time: P = 0.011). More specifically, after anodal tsDCS (Fig. 1A) RMT increased (post hoc analysis anodal tsDCS: T0_A vs. B_A: 107.33 ± 3.3%, P = 0.006; T30_A vs. B_A: 108.37 ± 3.2%, P = 0.002) whereas after cathodal tsDCS (Fig. 1B and Fig. 2A) it remained unchanged (post hoc analysis, cathodal tsDCS: T0_C vs. B_C: 96.83 ± 2.3%, P = 0.15; T30_C vs. B_C: 100.60 ± 2.1%, P = 0.8).

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Fig. 1.

A and B: lower limb motor evoked potentials (MEPs) before (baseline), immediately after (T0), and at 30 min after (T30) anodal (A) or cathodal (B) transcutaneous spinal direct current stimulation (tsDCS) in a representative subject. Each trace is the superimposition of 5 sweeps. Table on right reports average values of resting motor threshold (RMT), MEP area, and MEP latency for the represented subject. Note that whereas anodal tsDCS decreased the MEP area at T0 and T30, cathodal tsDCS increased the MEP area. Vertical arrows represent the stimuli. C and D: upper limb MEPs before (baseline), immediately after (T0), and at 30 min after (T30) anodal (C) or cathodal (D) tsDCS in a representative subject. Each trace is the superimposition of 5 sweeps. Table on right reports average values of RMT, MEP area, and MEP latency for the represented subject. Note that neither anodal nor cathodal tsDCS affected MEPs. Vertical arrows represent the stimuli.

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Fig. 2.

A and B: effects of tsDCS on RMT (A) and MEP area (B) when responses were recorded from abductor hallucis muscle (AH; data are expressed as % of baseline). Group data are presented as mean ± SE changes induced by anodal or cathodal tsDCS immediately after current offset (T0) and 30 min later (T30) (error lines are SE). Note that anodal and cathodal tsDCS induced significantly different, opposite changes in RMT and MEP area. C and D: effects induced by tsDCS on RMT (C) and MEP area (D) when responses were recorded from abductor digiti minimi (ADM) muscles. Group data are presented as mean ± SE changes induced by anodal or cathodal tsDCS immediately after current offset (T0) and 30 min later (T30) (error lines are SE). Neither anodal nor cathodal tsDCS significantly changed RMT or MEP area. **P < 0.05. N.S., not significant.

MEP area was also modulated after tsDCS (2-way ANOVA, factor stimulation: P = 0.96, factor time: P = 0.78; interaction stimulation × time: P = 0.008) (Fig. 2B): whereas after anodal tsDCS MEP area failed to change (post hoc analysis anodal tsDCS: T0_A vs. B_A: 66.09 ± 9.1%, P = 0.24; T30_A vs. B_A: 58.12 ± 10.48%, P = 0.13), after cathodal tsDCS MEP area increased (post hoc analysis cathodal tsDCS: T0_C vs. B_C: 139.71 ± 12.9%, P = 0.018; T30_C vs. B_C: 132.74 ± 22.0%, P = 0.02).

In conclusion, anodal tsDCS increases RMT whereas cathodal tsDCS increases the MEP area in lower limb muscles.

tsDCS effects in upper limb muscles.

No differences were found between anodal and cathodal tsDCS in baseline values for any of the measured variables in the upper limb muscles. Neither anodal nor cathodal tsDCS induced changes in F-wave variables (Table 1).

The two-way ANOVA disclosed no anodal or cathodal tsDCS-induced effect on MEP variables (Fig. 1, C and D, Fig. 2, C and D). RMT did not change over time and across sections (Fig. 2C; 2-way ANOVA, factor stimulation: P = 0.54, factor time: P = 0.14; interaction stimulation × time: P = 0.48), nor did MEP area (Fig. 2D; 2-way ANOVA, factor stimulation: P = 0.58, factor time: P = 0.63; interaction stimulation × time: P = 0.23). MEP latency was not affected by stimulation (2-way ANOVA, factor stimulation: P = 0.26; interaction stimulation × time: P = 0.29) but showed a nonspecific time-related increase at T30 compared with baseline (2-way ANOVA, time P = 0.013; post hoc analysis: baseline vs. T30 103.53 ± 0.95%, P = 0.011).

DISCUSSION

Whereas tsDCS leaves H reflex, F wave, and upper limb RMT and MEP size unchanged, it modulates the excitability in corticospinal projections to lower limb muscles for at least 30 min after stimulation offset, inducing polarity-dependent excitability changes: anodal tsDCS significantly increases RMT, whereas cathodal stimulation increases MEP area.

The absence of F wave changes in our experiments therefore argues against the occurrence of changes in postsynaptic motor neuronal excitability after tsDCS. The absence of Hmax-to-CMAPmax ratio changes in this and a previous study from our group (Cogiamanian et al. 2011) agrees with previous observations (Lamy et al. 2012; Winkler et al. 2010).

The tsDCS-induced corticospinal excitability changes at lower limb level are in line with our previous observation that tsDCS modulates conduction along human spinal ascending pathways (Cogiamanian et al. 2008; Truini et al. 2011) and are consistent with the effects of anodal spinal DC on motor potentials elicited by cortical stimulation in the mouse triceps surae (Ahmed 2011).

How tsDCS influences the corticospinal system remains hypothetical. First, because tDCS influences neurotransmitters in the brain (Rango et al. 2008), tsDCS could do the same in the human spinal cord, ultimately modulating the corticospinal output as in animals (Ahmed and Wieraszko 2012). As recently shown in animals (Ahmed 2013), cathodal tsDCS can amplify segmental responses to supraspinal drive by increasing glutamate release at the spinal level, although mice typically lack the monosynaptic corticomotor neuronal synapse of higher primates. Another possibility is that tsDCS could influence neural activity in ascending spinal pathways, ultimately modulating the excitability in their cortical targets including the motor areas, as changes in RMT suggest. Possible support for a cortical mechanism comes from a report that invasive spinal stimulation seems to modulate intracortical facilitation (Schlaier et al. 2007). Thus our data expand, rather than being simply contradictory, previous knowledge on putative tsDCS targets, including supraspinal, and possibly polarity-specific, effects of spinal current polarization; this possibility also agrees with recent evidence in rats that noninvasive spinal stimulation modulates the activity of gracile nucleus and primary somatosensory cortex (Aguilar et al. 2011).

Finally, tsDCS could influence the conductive properties of the corticospinal tract, for example, by decreasing/increasing the number of axons conducting an action potential. For instance, anodal tsDCS can induce a hyperpolarizing conduction block, thus blocking action potentials along the pyramidal tract (Bhadra and Kilgore 2004). However, given that we used low current intensities, anodal block could not be the sole explanation for the effects of anodal tsDCS; moreover, it is known that also in routinary electrodiagnostic testing geometry and tissue distribution of electrical fields are additional critical parameters for inducing a hyperpolarizing block (Dreyer et al. 1993; Kirshblum et al. 1998).

Although the mechanisms underlying the tsDCS-induced changes in the corticospinal system remain speculative, our finding that anodal tsDCS seems mainly to affect the RMT whereas cathodal tsDCS predominantly influences MEP area is intriguing. A possible explanation is that the mechanisms underlying cathodal and anodal tsDCS differ and could have different putative circuit(s)-pathway(s)-neurotransmitters, i.e., anodal current might preferentially act on one target system, whereas cathodal current acts on another. This possibility agrees with evidence that anodal and cathodal brain tDCS act through different brain neurotransmitters: for instance, whereas anodal tDCS reduces GABA, cathodal tDCS decreases glutamate (Stagg et al. 2009). Increase in MEP area after cathodal tsDCS is in line with previous reports (Aguilar et al. 2011; Ahmed 2011, 2013; Alanis 1953; Eccles et al. 1962) and agrees with data in animals showing an increased recruitment of larger motor units after cathodal polarization (Ahmed and Wieraszko 2012); as suggested in a recent work by our group, cathodal, but not anodal, stimulation could have a transsynaptic effect mediated by spinal interneurons likely involving Renshaw cell network (Bocci et al. 2014).

Among methodological issues related to our study the first is that to avoid subjecting participants to another experimental session, we decided not to test them under sham conditions. Sham testing was also unnecessary given that even though changes induced by cathodal tsDCS and anodal tsDCS go in opposite directions, subjects cannot distinguish between the two polarities. We therefore considered each polarity as the best possible control for the other, as previously reported (Cogiamanian et al. 2008; Lamy and Boakye 2013a; Truini et al. 2011). Besides, as recently shown by Kessler and colleagues (Kessler et al. 2012), sham stimulation may be an inappropriate control condition for some studies, because sensory side effects seem to be more frequent and severe in active than in sham tDCS.

A second methodological issue concerns possible pitfalls concerning the use of the H reflex and the F wave to assess spinal motor neuron excitability. The absence of H-reflex changes suggests no modification to small motor neurons, and the lack of F-wave effects rules out changes in large motor neurons (McNeil et al. 2013). However, the classical view that the H reflex and the F wave represent separate and complementary events at spinal level, i.e., presynaptic inhibition versus changes in intrinsic motor neuron excitability (Fisher 1992; Leis et al. 1995), is questionable. In fact, while the H reflex could be also affected by postactivation depression and changes in axonal excitability itself (McNeil et al. 2013; Pierrot-Deseilligny et al. 1981), many reports have suggested that F waves offer only a flawed measure of motor neuron excitability (Hultborn and Nielsen 1995).

A further important point is to compare our data with those of Lim and Shim (2011), who found that cervical spinal DC stimulation influences upper limb MEPs. However, they did not report polarity-specific effects. Their results cannot be compared with ours because they studied a different anatomical region, with a different recording montage and stimulation intensity, and used smaller electrodes. Finally, there are known features in how corticospinal excitability differs between the upper and lower body, which may account, at least in part, for differences between our results and data obtained by Lim and Shin. In particular, monosynaptic corticomotor neuronal projections, with fast-conducting motor units, are more prominent for hand than for proximal arm or lower limb muscles (Brouwer and Ashby 1992; Dalpozzo et al. 2002; Palmer and Ashby 1992); in this view, the lack of changes in MEP amplitude after anodal tsDCS may be caused by the greater desynchronization of corticomotor neuronal input compared with upper limb muscles, related to the involvement of fibers with different sizes or activation of polysynaptic descending pathways.

Overall, our data support the conclusion that tsDCS induces changes in corticospinal tract excitability. The first clinical observations with tsDCS are encouraging: Hubli et al. (2013) found that anodal tsDCS can improve gait in patients with spinal cord injury. Together with a previous report describing how tsDCS influences ascending spinal pathways (Aguilar et al. 2011), the present experiments suggest that the spinal cord could act as a “highway” for conveying tsDCS-induced changes to the brain, thereby inducing suprasegmental effects in the brain and brain stem. Because tsDCS is simple, safe, and noninvasive, our observation opens the way to new approaches using this technique in widely ranging neurological conditions characterized by corticospinal and spinal cord dysfunction and possibly even in brain disorders.

GRANTS

This work was supported by FISM (Fondazione Italiana Sclerosi Multipla)-2009/R21.

DISCLOSURES

M. Vergari, S. Marceglia, F. Cogiamanian, and A. Priori are founders and shareholders of Newronika srl, Milan, Italy, a spin-off company of the University of Milan and of the Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico.

AUTHOR CONTRIBUTIONS

Author contributions: T.B., F.C., F.S., and A.P. conception and design of research; T.B., M.V., V.C., and F.C. performed experiments; T.B., S.M., M.V., F.C., F.S., and A.P. interpreted results of experiments; T.B. and S.M. drafted manuscript; T.B., S.M., M.V., V.C., and A.P. edited and revised manuscript; T.B., S.M., M.V., V.C., F.C., F.S., and A.P. approved final version of manuscript; S.M. analyzed data; M.V. and V.C. prepared figures.

ACKNOWLEDGMENTS

REFERENCES