Neuromodulation: Technology at the Neural Interface Received: December 3, 2014
Revised: February 9, 2015
Accepted: February 25, 2015
(onlinelibrary.wiley.com) DOI: 10.1111/ner.12298
Spinal Direct Current Stimulation Modulates Short Intracortical Inhibition Tommaso Bocci, MD*†; Davide Barloscio, MD*; Maurizio Vergari, MD‡; Andrea Di Rollo, MD§; Simone Rossi, MD, PhD†; Alberto Priori, MD‡; Ferdinando Sartucci, MD*§¶1 Objective: Transcutaneous spinal direct current stimulation (tsDCS) is a new and safe technique for modulating spinal cord excitability. We assessed changes in intracortical excitability following tsDCS by evaluating changes in cortical silent period (cSP), paired-pulse short intracortical inhibition (SICI), and intracortical facilitation (ICF). Materials and Methods: Healthy subjects were studied before (T0) and at different intervals (T1 and T2) after anodal, cathodal, and sham tsDCS (20’, 2.0 mA) applied over the thoracic spinal cord (T10–T12). We assessed changes in cSP, SICI (interstimulus interval, ISI = 3 ms) and ICF (ISI = 10 ms). Motor-evoked potentials (MEPs) were recorded from first digital interosseus (FDI) and tibialis anterior (TA) muscles. Results: Cathodal tsDCS increased MEP amplitudes at interstimulus interval of 3 ms, while anodal one elicited opposite effects (FDI: p = 0.0023; TA: p = 0.0004); conversely, tsDCS left MEP amplitudes unchanged at ISI of 10 ms (FDI: p = 0.39; TA: p = 0.45). No significant change in cSP duration was found from upper limb (p = 0.81) and lower limb (p = 0.33). Conclusion: tsDCS modulates inhibitory GABA(A)ergic drive, as assessed by SICI, without interfering with cSP and ICF. The possibility to interfere with cortical processing makes tsDCS a useful approach to modulate spinal drive through nonspinal mechanisms. tsDCS could also represent an early rehabilitation strategy in patients with acute brain lesions, when other noninvasive brain stimulation (NIBS) tools are not indicated due to safety concerns, as well as in the treatment of spinal diseases or pain syndromes. Keywords: Cortical silent period, motor system, short intracortical facilitation, short intracortical inhibition, transcutaneous spinal direct current stimulation, tsDCS Conflict of Interest: Drs. Vergari and Priori are founders and shareholders of Newronika srl, Milan, Italy. The other authors report no conflicts of interest.
INTRODUCTION
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Transcutaneous spinal direct current stimulation (tsDCS ) (1–3) is a simple, noninvasive and well-tolerated technique for modulating spinal cord excitability in humans and animals (4–6). tsDCS consists in delivering a constant direct current (DC) over the spinal cord though a pair of sponge electrodes, one placed over the spinal cord and the other (the reference) over the right arm (7–10). DC stimulation ranges from 1.5 to 2.5 mA, with effects lasting from minutes to hours (7–10). By analogy with the effects of direct currents on peripheral nerves, it has been proposed that anodal stimulation leads to a hyperpolarizing “conduction block,” although a more complex interaction between synaptic and axonal mechanisms has been proven in mice (11,12). Conversely, two synaptic, nonmutually exclusive, mechanisms of cathodal polarization have been hypothesized, ultimately leading to a facilitation of spinal drive: an inhibition of γ-aminobutyric acid(GABA)ergic system and a direct overexcitation of postsynaptic neurons, probably by increasing glutamate release at spinal level (5). A prominent synaptic action of cathodal stimulation on spinal interneurons was recently confirmed in humans (13). Previous studies showed that thoracic anodal tsDCS depresses the cervico-medullary PTN-SEP component (P30) and also moduwww.neuromodulationjournal.com
lates postactivation H-reflex dynamics (8,9). Subsequent studies found that tsDCS modulates the flexion reflex in the human lower limb (1). Besides reducing amplitude of the laser-evoked potentials (LEPs) derived from lower limbs, anodal tsDCS seems also to impair
Address correspondence to: Ferdinando Sartucci, MD, Department of Clinical and Experimental Medicine, Unit of Neurology, Pisa University Medical School, Via P. Savi, n. 40; I 56126, Pisa, Italy. Email: [email protected] * Department of Clinical and Experimental Medicine, Unit of Neurology, Pisa University Medical School, Pisa, Italy; † Department of Neurological and Neurosensorial Sciences, Neurology and Clinical Neurophysiology Section, Brain Investigation and Neuromodulation Lab., Azienda Ospedaliera Universitaria Senese, Siena, Italy; ‡ Department of Neurological Sciences, University of Milan, Fondazione IRCCS Ospedale Maggiore Policlinico, Milan, Italy; § Department of Clinical and Experimental Medicine, Cisanello Neurology Unit, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy; and ¶ CNR Neuroscience Institute, Pisa, Italy For more information on author guidelines, an explanation of our peer review process, and conflict of interest informed consent policies, please go to http:// www.wiley.com/bw/submit.asp?ref=1094-7159&site=1 1
Current address: Ferdinando Sartucci, Unit of Neurology, Cisanello Hospital, Via Paradisa, n. 2; I 56124, Pisa, Italy.
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tsDCS AND INTRACORTICAL EXCITABILITY conduction in the ascending nociceptive spinal pathways, thus increasing pain tolerance in healthy subjects (14). Along this view, a role of tsDCS in the treatment of idiopathic restless legs syndrome has been recently proven (15). However, the effects of tsDCS on the corticospinal excitability are only partly understood. Changes following anodal or cathodal polarization were reported to be not polarity dependent, both leading to a facilitation of corticospinal outcome as revealed by the significant increase of the amplitude of motor-evoked potentials (MEPs) (10,16). Moreover, despite its growing use, to date whether and how tsDCS induces functional changes in the human brain are still unknown. First, that could be helpful to unveil new tsDCS targets, thus raising direct stimulation as a promising therapeutic tool in managing a number of human diseases. Second, tsDCS could also represent an intriguing functional model of spinal cord injury (SCI), in order to explore cortical mechanisms of motor and sensory recovery in the spinal damage. A recent study in rats was encouraging: Aguilar and colleagues showed that tsDCS is able to modulate the activity of gracile nucleus and primary somatosensory cortex (S1) (17). In particular, anodal tsDCS increases the spontaneous activity and decreases the amplitude of the local field potentials (LFPs) in the gracile nucleus and S1, whereas cathodal tsDCS induces opposite effects. These findings fit with data in rats showing a dramatic decrease of electroencephalogram (EEG) activity and anesthetic requirement following a complete spinal cord transection (18,19). The aim of our study was to assess whether tsDCS has or no effects on intracortical excitability; we evaluated changes in cortical silent period (cSP), paired-pulse short intracortical inhibition (SICI); and intracortical facilitation (ICF). The paired-pulse transcranial magnetic stimulation (TMS) protocol offers a unique opportunity to explore inhibitory and facilitatory circuitry of the human motor cortex (20). When a subthreshold conditioning pulse (S1) and a suprathreshold test pulse (S2) are applied to the motor cortex through the same coil, the test response is inhibited at interstimulus intervals (ISIs) between 1 and 5 ms (short-interval intracortical inhibition, SICI), while it is facilitated at ISIs of 6–30 ms (intracortical facilitation, ICF); it has been shown that phenomena underlying the generation of ICF and SICI occur at cortical level (21–23), acting differently during execution or suppression of voluntary movements (24,25).
MATERIALS AND METHODS Subjects Ten healthy volunteers (four women and six men, mean age ± SD: 26.5 ± 4.4 years) with no history of neurological disorders were enrolled in the study. No subject was taking medications at the time of, or one month before, the inclusion in the study, and they all had suspended alcohol or caffeine consumption at least 48 hours before. Written informed consent was obtained from all subjects prior to inclusion in the study. Experiments were approved by the local ethical committee and followed the Declaration of Helsinki.
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Transcranial Magnetic Stimulation A Magstim super rapid transcranial magnetic stimulator (2.2 T maximum field output; Magstim Company, Dyfed, UK), connected to either a standard flat coil (outer diameter 12.5 cm) or an eightshaped focal coil (wing diameters of 70 mm), was used. cSP duration was assessed following single pulse stimulation of contralateral motor cortex delivered by the flat coil; the coil was kept in a constant position centered over the vertex for both upper and lower limb; for the upper limb, one edge of the coil was slightly tilted toward the hemisphere to be stimulated. We calculated the mean cSP duration based on trial-by-trial measurements of the cSP duration (five trials per muscle). cSP following each TMS pulse given at 150% of the resting motor threshold (RMT) was determined while subjects activated FDI or TA muscle at approximately 50% of the maximum voluntary contraction, monitored by an isometric dynamometer (26). RMT was defined as the minimum stimulator output that induces motor-evoked potentials (MEPs) of more than 50 μV in at least 5 out of 10 trials when FDI or TA muscle was completely relaxed (27). In each trial, the cSP is measured as the time elapsing from the onset of the MEP until the recurrence of voluntary tonic EMG activity (28). However, voluntary EMG activity does not recover abruptly, but gradually, and a silent period with a biphasic appearance may sometimes be recorded. To avoid both inconveniences, we assumed that if the EMG activity reaches or exceeds the pre-TMS baseline level and lasts for at least 50 ms, reoccurring EMG activity marks the end of the cSP (28). As concerns paired-pulse TMS, we adopted the original protocol proposed by Kujirai and colleagues (21). ICF and SICI were obtained at rest with a subthreshold conditioning stimulus (S1) followed by a suprathreshold test stimulus (S2) at ISIs of 10 and 3 ms, respectively. Test stimuli were set at an intensity of 125% RMT. The conditioning stimuli were set at 75% of the RMT, corresponding at about 90% of the active motor threshold (AMT) (29,30). For pairedpulse recordings, full muscle relaxation is fundamental (31) and was ensured by providing the subjects with audiovisual feedback of the raw EMG at high gain (microV). As it has recently been shown that tsDCS affects RMT (16), we readjusted both test and conditioning stimuli after spinal polarization. For FDI muscle, the handle of the eight-shaped focal coil pointed backwards and rotated about 45° to the mid-sagittal line. The induced current was perpendicular to the central sulcus in the PA direction and was optimal to activate the corticospinal neurons trans-synaptically. The optimal coil position to evoke a reliable MEP, from FDI and TA muscles, was marked on the scalp to ensure identical placement of the coil throughout the experiments.
tsDCS With participants lying supine on a comfortable couch, tsDCS (2.5 mA, 20 min) was delivered by a constant current programmable electrical stimulator (HDCStim, Newronika, Milan, Italy) connected to a pair of rectangular electrodes, one on the thoracic spinal cord (over the spinous process of the tenth thoracic vertebra, from 9th to 11th vertebra, with the major axis parallel to spinal cord) and the other above the right shoulder (1,7). tsDCS electrodes were thick
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Recordings Electromyographic (EMG) recordings were made by two standard nonpolarizable Ag/AgCl surface electrodes (diameter 9 mm; Technomed Europe © 2013, AE Maastricht-Airport, the Netherlands), one placed over the belly of the contralateral first digital interosseus (FDI) muscle, and the other on the skin overlying the
first metacarpophalangeal joint of the first finger of the left hand; for lower limbs, MEPs were recorded through one electrode placed over the belly of the tibialis anterior (TA) muscle and the other over its distal tendon.
BOCCI ET AL. (6 mm) rectangular pieces of saline-soaked synthetic sponge (7 × 5 cm, 35 cm2). We applied current at a density of 0.071 mA/cm2, below the threshold values for tissue damage (32,33). The wide electrode surface avoided the possible harmful effects of highcurrent density. Apart from occasional and short-lasting tingling sensation below the electrodes, tsDCS remained below the conscious sensory threshold throughout the experimental session. tsDCS polarity (sham, cathodal, or anodal) refers to the electrode over the spinal cord. For a sham tDCS, the current was turned on only for 5 sec at the beginning of the sham session and then it was turned off in a ramp-shaped fashion, which induces initial skin sensations indistinguishable from real tDCS. At experimental debriefing, subjects were not able to discriminate between the applied anodal, cathodal, and sham tDCS.
Experimental Design Subjects were studied before and after sham, anodal cathodal tsDCS. Different sessions on the same volunteer were separated by at least one week to avoid possible carry-over effects, and the order of interventional protocols was randomized and balanced across subjects. The subjects were blinded about tsDCS polarity. cSP, SICI, and short intracortical facilitation (SICF) were assessed before tsDCS (T0), immediately after (T1), and at 60 min after tsDCS offset (T2). For all the electrophysiological recordings, we chose the left side to avoid interference from the reference placed over the contralateral shoulder.
Statistical Analysis Values are reported as mean ± 1 standard deviation (SD). MEP amplitudes were measured peak to peak. The MEP amplitudes evoked by paired-pulse stimulation were expressed as a percentage
of the mean MEP amplitude of test stimulus (S2) alone (34,35). As a preliminary evaluation to prove the reliability of our data, raw values at baseline were compared among different sessions (one-way repeated measure analysis of variance [ANOVA], STATISTICA 5.5, StatSoft Inc., Tulsa, OK, USA). The tsDCS-induced changes in each variable were then tested with a two-way repeated measure ANOVA with main factors “stimulation,” three levels (sham, anodal, and cathodal), and “time,” three levels (T0, T1, and T2). The Greenhouse–Geisser ε correction for nonsphericity was applied when necessary. After Bonferroni correction, significance level was set at p < 0.007.
RESULTS Raw data ± 1 SD are summarized in Table 1 (for recordings made from FDI) and in Table 2 (TA muscle). Cortical Silent Period Values at baseline ranged from 162.2 to 232.1 ms and from 141.8 to 215.5 ms, for FDI and TA muscles, respectively, in line with those previously reported in literature (36), and did not differ among experimental conditions (p > 0.3). tsDCS did not modify cSP duration (FDI: F(4, 81) = 0.18, p = 0.9; TA: F(4, 81) = 0.1, p = 0.9, “stimulation × time” interaction). When compared with sham stimulation, neither anodal (FDI: F(2, 54) = 0.37, p = 0.69; TA: F(2, 54) = 0.11, p = 0.87) or cathodal polarization (FDI: F(2, 54) = 0.19, p = 0.83; TA: F(2, 54) = 0.45, p = 0.51) induced significant changes (Fig. 1). Paired-Pulse TMS As for cSP, spinal polarization left ICF unchanged over time (FDI: F(4, 81) = 0.41, p = 0.81; TA: F(4, 81) = 1.18, p = 0.33, “stimulation × time”
Table 1. Row Data Recorded From FDI Muscle (Expressed as Mean Value ± 1 Standard Deviation [SD]). First digital interosseus (FDI) cSP (ms)
Mean SD Mean SD Mean SD
SICI (% of S2 alone) ICF (% of S2 alone)
aT0
aT1
aT2
cT0
cT1
cT2
shT0
shT1
shT2
199.7 37.7 50.2 12.1 123.1 11.8
197.6 32.9 30.2 7.9 122.7 11.2
205.0 29.8 29.9 8.1 120.3 12.6
198.0 37.1 50.7 9.5 122.6 8.7
199.5 44.9 107.2 14.3 120.8 11.8
203.1 34.5 103.3 17.2 126.1 7.8
199.5 31.3 51.8 10.5 119.1 12.3
208.3 30.6 50.4 11.5 122.9 9.1
198.3 29.7 53.1 10.4 116.3 10.2
MEP amplitudes for ISI set at 3 (SICI) and 10 ms (ICF) are expressed as percentage of test stimulus (S2) alone (a = anodal stimulation; c = cathodal stimulation; sh = sham condition). cSP, cortical silent period; ICF, intracortical facilitation; SICI, short intracortical inhibition.
Table 2. Row Data Recorded From TA Muscle (Expressed as Mean Value ± 1 Standard Deviation [SD]). Tibialis anterior (TA) cSP (ms) SICI (% of S2 alone) ICF (% of S2 alone)
Mean SD Mean SD Mean SD
aT0
aT1
aT2
cT0
cT1
cT2
shT0
shT1
shT2
178.4 36.9 50.9 6.9 121.8 9.0
174.5 30.6 32.1 6.5 123.7 9.8
179.2 32.9 29.9 6.1 118.6 9.7
183.2 34.8 52.2 14.9 118.9 6.7
185.0 29.7 94.5 13.4 123.5 5.7
180.7 35.1 98.7 15.8 127.1 8.7
172.5 52.7 53.3 8.5 119.2 8.2
180.0 57.0 53.8 9.3 119.6 8.8
174.0 42.5 55.7 14.1 120.0 10.1
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MEP amplitudes for ISI set at 3 (SICI) and 10 ms (ICF) are expressed as percentage of test stimulus (S2) alone (a = anodal stimulation; c = cathodal stimulation; sh = sham condition). cSP, cortical silent period; ICF, intracortical facilitation; SICI, short intracortical inhibition.
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tsDCS AND INTRACORTICAL EXCITABILITY
Figure 1. Cortical silent period (cSP). tsDCS left cSP duration unchanged over time, when recordings were made from (a) FDI or (b) TA muscle. On the right: representative traces recorded from TA muscle in the same subject showing no modification between anodal and cathodal stimulation. FDI, first digital interosseus; TA, tibialis anterior; tsDCS, transcutaneous spinal direct current stimulation.
Figure 2. Intracortical facilitation (ICF). As for cSP, tsDCS left MEPs amplitude unchanged when stimuli were administered at ISI = 10 ms (data are expressed as percentage of the mean MEP amplitude elicited by test stimulus, S2, alone). Representative traces (right), recorded from TA muscle, show no modification at T1 and T2, following either anodal or cathodal polarization, compared with the facilitated MEP at T0. The MEP obtained following the test stimulus (S2) alone was shown at the top. cSP, cortical silent period; MEP, motor-evoked potential; tsDCS, transcutaneous spinal direct current stimulation.
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obtained by paired-pulse stimulation at ISI = 10 ms. This trend was confirmed at each time point, both for FDI and TA muscle (p > 0.3). Conversely, tsDCS significantly changed MEP amplitudes at ISI of 3 ms (Fig. 3), recorded both by FDI (F(4,81) = 36.9, p < 0.0001,
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interaction: Fig. 2); in particular, when compared with sham condition, neither anodal (FDI: F(2, 54) = 0.21, p = 0.81; TA: F(2, 54) = 0.3, p = 0.74) or cathodal polarization (FDI: F(2, 54) = 1.73, p = 0.19; TA: F(2, 54) = 1.05, p = 0.36) significantly modified MEP amplitudes
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Figure 3. Short intracortical inhibition (SICI). Cathodal tsDCS significantly improved MEPs amplitude at ISI = 3 ms, while anodal one elicited opposite effects (data are expressed as percentage of the mean MEP amplitude elicited by test stimulus alone). Representative traces (on the top) were recorded in the same subject from FDI (left) and TA (right) muscles; for each muscle and polarity, the MEP obtained following the test stimulus (S2) alone was also shown. *p < 0.05; **p < 0.01. FDI, first digital interosseus; MEP, motor-evoked potential; TA, tibialis anterior; tsDCS, transcutaneous spinal direct current stimulation.
“stimulation × time” interaction) and TA muscle (F(4,81) = 25.0, p < 0.0001). When analyzed separately, cathodal tsDCS improved MEP size compared with sham condition (FDI: F(2,54) = 31.9, p < 0.0001; TA: F(2,54) = 15.9, p < 0.0001), while anodal one elicited opposite changes (vs. sham: F(2,54) = 6.56, p = 0.0028; F(2,54) = 8.6, p = 0.0006 for FDI and TA muscles, respectively; vs. cathodal: F(2,54) = 64.5, p < 0.0001; F(2,54) = 46.9, p < 0.0001). The effects remained stable at T1 and T2 for both cathodal (FDI: T1 vs. T0: p < 0.0001, T2 vs. T0: p < 0.0001; TA: T1 vs. T0: p < 0.0001, T2 vs. T0: p < 0.0001) and anodal polarization (FDI: T1 vs. T0: p = 0.0087, T2 vs. T0: p = 0.0076; TA: T1 vs. T0: p = 0.012, T2 vs. T0: p = 0.011).
DISCUSSION
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The main finding of our work is that tsDCS is able to modulate intracortical excitability in a polarity specific manner. In particular, modifications of SICI without interfering with cSP and ICF prompt a specific modulation of inhibitory GABA(A)ergic drive within primary motor cortex. While SICI is likely to be mediated by GABA(A) receptors (37–39), ICF hinges on glutamatergic pathways (40,41), although a more complex interaction between inhibitory and excitatory circuits has been suggested for its generation (22,42,43); conversely, cSP mainly reflects postsynaptic GABA(B)ergic function, with spinal mechanisms partially contributing to the early part of EMG inhibition (42,44,45). Previous studies have reported a significant effect of tsDCS both on postactivation depression and recruitment curve of www.neuromodulationjournal.com
H-reflex (8,9); although modulation of segmental circuits is likely associated with supraspinal intracortical excitability changes, whether and how these modifications take place are still a matter of debate. In particular, tsDCS may have polarity-specific effects on spinal pathways different from those induced on supraspinal targets. The intriguing possibility to modulate the functional state of the brain by influencing spinal drive was previously suggested by works using invasive spinal cord stimulation (SCS). In particular, SCS was demonstrated to be effective in restoring locomotion in animal models of Parkinson’s disease, paralleled by a disruption of antikinetic low-frequency synchronous corticostriatal oscillations (46,47). In humans, it is known that alternating currents epidurally delivered to the posterior columns of the spinal cord are able to deeply modify sensory processing at thalamic relays and cortical levels (48). More importantly, possible support for a cortical mechanism in humans comes from a recent report where SCS seems to enhance the intracortical facilitation in patients with neuropathic pain (49). However, SCS is a useful tool different from tsDCS, using, for instance, intensities above perceptive threshold; moreover, its mechanisms of action are better understood, ranging from spinal and supraspinal targets to hemodynamic changes (50,51). Here, different from SCS, noninvasive spinal stimulation seems to specifically interfere with cortical inhibitory networks, not with facilitatory processing. In this scenario, the mechanisms by which tsDCS could modulate cortical activities, especially for upper limb muscles, remain elusive.
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tsDCS AND INTRACORTICAL EXCITABILITY In fact, while dorsal tsDCS is likely to affect both descending and ascending pathways to TA, it does not directly alter target pathways to and from FDI muscle. Possible explanation comes from spinal injuries studies, describing an increased cortical representation of nonimpaired upper limb muscles in paraplegic patients (52). This is also in line with TMS investigations in paraplegics showing an increased representation of preserved muscles proximal to the lesion level (53). Specifically, expansion of motor maps into the deafferented cortex is commonly attributed both to unmasking of the latent intracortical connections between hemispheres and to activity-dependent changes underlying the so-called long-term potentiation (LTP) (54–56). Along this view, Topka and colleagues reported that TMS activated a large fraction of motorneuron pools and evoked MEPs with shorter latencies from a large number of scalp positions in abdominal muscles rostral to the level of SCI (57). Others suggested that SCI is also associated with a high degree of synergic co-activation of muscles proximal to the lesion level (58). Lack of intracortical GABA(A)ergic inhibition may favor, at least in part, all these changes. From a molecular point of view and by analogy with animal models, we could speculate that the effects of invasive spinal polarization could be induced by the modulation of indirect spinal projections to noradrenergic locus coeruleus (LC) neurons, which has widespread projections to the neocortical brain (59–62). Alternatively, a critical role in brain plasticity could be played by a dynamic modulation of serotonergic ascending pathways, especially through parallel and partially overlapping projections arising from the median and dorsal raphe nuclei (63–66). Although not directly investigated in the present study, as serotonergic projections seem to participate in the regulation of different functional systems (motor, somatosensory, limbic), tsDCS may ultimately modulate this connectivity.
ways (74). For the calculation of cSP, we adopted one of the two more used and accepted protocols proposed by an ad hoc committee of the International Federation of Clinical Neurophysiology (IFCN) (28), although some excellent papers have recently described alternative methods to improve accuracy for the cSP estimation (75); however, these methods are not standardized yet and require devices and software for data analysis not available in many laboratories. Finally, lack of intracortical effects, following tsDCS, has been recently reported elsewhere (16); the results, however, can difficultly be compared with ours because they studied a different anatomical region, with a different recording montage and stimulation intensities.
CONCLUSIONS The tsDCS could be of particular interest as a noninvasive, safe, promising therapeutic tool in managing a number of human diseases. This technique could be useful especially as an early rehabilitation strategy in patients with acute brain lesions, when other noninvasive brain stimulation (NIBS) tools are not indicated due to safety concerns, or even in the treatment of neurological disorders characterized by abnormal interhemispheric processing. In addition, the possibility to modulate supraspinal and intracortical processing of motor inputs makes tsDCS a useful approach, complementary to either SCS or NIBS techniques, to modify spinal drive through nonspinal mechanisms. Our results prompt further investigations, especially in patients with spinal cord injuries, brain diseases, or pain syndromes.
Acknowledgements
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We gratefully acknowledge the participation of all subjects, as well as Mr. C. Orsini and Ms. L. Parenti for their excellent technical assistance. We also thank Prof. M. Caleo at Scuola Normale Superiore, Pisa, for his support in language editing. The paper was supported in part by the Italian operating and development MIUR PRIN grant year 2006, n. 2006062332_002.
Authorship Statement Tommaso Bocci designed the study, collected the data and assisted in writing the manuscript. Davide Barloscio participated in subject recruitment, data collection and assisted in writing the manuscript. Maurizio Vergari assisted with data analysis and writing the manuscript. Andrea Di Rollo assisted with subject recruitment and writing the manuscript. Simone Rossi and Alberto Prioro helped design the study. Ferdinando Sartucci assisted in study design and writing of the manuscript.
How to Cite this Article: Bocci T., Barloscio D., Vergari M., Di Rollo A., Rossi S., Priori A., Sartucci F. 2015. Spinal Direct Current Stimulation Modulates Short Intracortical Inhibition. Neuromodulation 2015; 18: 686–693
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Methodological Issues and Possible Pitfalls From the beginning, our group has adopted the montage we used here, with the active electrode placed over the lower thoracic spinal cord and the return one over the right arm. Although different settings and stimulation parameters have been proposed (10,16), the “monopolar” montage dampens the spread of the current toward the higher spinal cord levels or to the brainstem, reducing at the same time interference between anodal and cathodal effects and decreasing cutaneous shunt (67). Equally important, longitudinal electrical fields, as those induced by this montage, are known to have potential implications for rehabilitation, as they both promote axonal regrowth and prevent fiber degeneration (68). Our study has some limitations. First, we did not assess the possibility to interfere with presynaptic GABA(B)ergic interneurons, likely involved in a late period of disinhibition, as their activity could be evaluated only by using a complex triple-stimulation paradigm (69). Second, we cannot exclude an influence of SICF on SICI, although this contamination occurs only at discrete intervals typically sparing the ISI of 3 ms and with stimulus intensities higher than those we used here (ISI ∼4.5 ms and S1 intensity >90% AMT) (70–72). Anywhere, SICF and SICI are strictly related each other and their effects converge on pyramidal neurons to elicit MEPs (73); altogether, we cannot easily rule out a modulation of both facilitatory and inhibitory intracortical pathways. Third, as cSP is also due to spinal mechanisms comprising motorneuron hyperpolarization and activation of inhibitory Renshaw network, it partly represents an indirect measure of the integrity of GABA(b)ergic intracortical path-
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Revised: February 9, 2015
Accepted: February 25, 2015
(onlinelibrary.wiley.com) DOI: 10.1111/ner.12298
Spinal Direct Current Stimulation Modulates Short Intracortical Inhibition Tommaso Bocci, MD*†; Davide Barloscio, MD*; Maurizio Vergari, MD‡; Andrea Di Rollo, MD§; Simone Rossi, MD, PhD†; Alberto Priori, MD‡; Ferdinando Sartucci, MD*§¶1 Objective: Transcutaneous spinal direct current stimulation (tsDCS) is a new and safe technique for modulating spinal cord excitability. We assessed changes in intracortical excitability following tsDCS by evaluating changes in cortical silent period (cSP), paired-pulse short intracortical inhibition (SICI), and intracortical facilitation (ICF). Materials and Methods: Healthy subjects were studied before (T0) and at different intervals (T1 and T2) after anodal, cathodal, and sham tsDCS (20’, 2.0 mA) applied over the thoracic spinal cord (T10–T12). We assessed changes in cSP, SICI (interstimulus interval, ISI = 3 ms) and ICF (ISI = 10 ms). Motor-evoked potentials (MEPs) were recorded from first digital interosseus (FDI) and tibialis anterior (TA) muscles. Results: Cathodal tsDCS increased MEP amplitudes at interstimulus interval of 3 ms, while anodal one elicited opposite effects (FDI: p = 0.0023; TA: p = 0.0004); conversely, tsDCS left MEP amplitudes unchanged at ISI of 10 ms (FDI: p = 0.39; TA: p = 0.45). No significant change in cSP duration was found from upper limb (p = 0.81) and lower limb (p = 0.33). Conclusion: tsDCS modulates inhibitory GABA(A)ergic drive, as assessed by SICI, without interfering with cSP and ICF. The possibility to interfere with cortical processing makes tsDCS a useful approach to modulate spinal drive through nonspinal mechanisms. tsDCS could also represent an early rehabilitation strategy in patients with acute brain lesions, when other noninvasive brain stimulation (NIBS) tools are not indicated due to safety concerns, as well as in the treatment of spinal diseases or pain syndromes. Keywords: Cortical silent period, motor system, short intracortical facilitation, short intracortical inhibition, transcutaneous spinal direct current stimulation, tsDCS Conflict of Interest: Drs. Vergari and Priori are founders and shareholders of Newronika srl, Milan, Italy. The other authors report no conflicts of interest.
INTRODUCTION
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Transcutaneous spinal direct current stimulation (tsDCS ) (1–3) is a simple, noninvasive and well-tolerated technique for modulating spinal cord excitability in humans and animals (4–6). tsDCS consists in delivering a constant direct current (DC) over the spinal cord though a pair of sponge electrodes, one placed over the spinal cord and the other (the reference) over the right arm (7–10). DC stimulation ranges from 1.5 to 2.5 mA, with effects lasting from minutes to hours (7–10). By analogy with the effects of direct currents on peripheral nerves, it has been proposed that anodal stimulation leads to a hyperpolarizing “conduction block,” although a more complex interaction between synaptic and axonal mechanisms has been proven in mice (11,12). Conversely, two synaptic, nonmutually exclusive, mechanisms of cathodal polarization have been hypothesized, ultimately leading to a facilitation of spinal drive: an inhibition of γ-aminobutyric acid(GABA)ergic system and a direct overexcitation of postsynaptic neurons, probably by increasing glutamate release at spinal level (5). A prominent synaptic action of cathodal stimulation on spinal interneurons was recently confirmed in humans (13). Previous studies showed that thoracic anodal tsDCS depresses the cervico-medullary PTN-SEP component (P30) and also moduwww.neuromodulationjournal.com
lates postactivation H-reflex dynamics (8,9). Subsequent studies found that tsDCS modulates the flexion reflex in the human lower limb (1). Besides reducing amplitude of the laser-evoked potentials (LEPs) derived from lower limbs, anodal tsDCS seems also to impair
Address correspondence to: Ferdinando Sartucci, MD, Department of Clinical and Experimental Medicine, Unit of Neurology, Pisa University Medical School, Via P. Savi, n. 40; I 56126, Pisa, Italy. Email: [email protected] * Department of Clinical and Experimental Medicine, Unit of Neurology, Pisa University Medical School, Pisa, Italy; † Department of Neurological and Neurosensorial Sciences, Neurology and Clinical Neurophysiology Section, Brain Investigation and Neuromodulation Lab., Azienda Ospedaliera Universitaria Senese, Siena, Italy; ‡ Department of Neurological Sciences, University of Milan, Fondazione IRCCS Ospedale Maggiore Policlinico, Milan, Italy; § Department of Clinical and Experimental Medicine, Cisanello Neurology Unit, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy; and ¶ CNR Neuroscience Institute, Pisa, Italy For more information on author guidelines, an explanation of our peer review process, and conflict of interest informed consent policies, please go to http:// www.wiley.com/bw/submit.asp?ref=1094-7159&site=1 1
Current address: Ferdinando Sartucci, Unit of Neurology, Cisanello Hospital, Via Paradisa, n. 2; I 56124, Pisa, Italy.
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tsDCS AND INTRACORTICAL EXCITABILITY conduction in the ascending nociceptive spinal pathways, thus increasing pain tolerance in healthy subjects (14). Along this view, a role of tsDCS in the treatment of idiopathic restless legs syndrome has been recently proven (15). However, the effects of tsDCS on the corticospinal excitability are only partly understood. Changes following anodal or cathodal polarization were reported to be not polarity dependent, both leading to a facilitation of corticospinal outcome as revealed by the significant increase of the amplitude of motor-evoked potentials (MEPs) (10,16). Moreover, despite its growing use, to date whether and how tsDCS induces functional changes in the human brain are still unknown. First, that could be helpful to unveil new tsDCS targets, thus raising direct stimulation as a promising therapeutic tool in managing a number of human diseases. Second, tsDCS could also represent an intriguing functional model of spinal cord injury (SCI), in order to explore cortical mechanisms of motor and sensory recovery in the spinal damage. A recent study in rats was encouraging: Aguilar and colleagues showed that tsDCS is able to modulate the activity of gracile nucleus and primary somatosensory cortex (S1) (17). In particular, anodal tsDCS increases the spontaneous activity and decreases the amplitude of the local field potentials (LFPs) in the gracile nucleus and S1, whereas cathodal tsDCS induces opposite effects. These findings fit with data in rats showing a dramatic decrease of electroencephalogram (EEG) activity and anesthetic requirement following a complete spinal cord transection (18,19). The aim of our study was to assess whether tsDCS has or no effects on intracortical excitability; we evaluated changes in cortical silent period (cSP), paired-pulse short intracortical inhibition (SICI); and intracortical facilitation (ICF). The paired-pulse transcranial magnetic stimulation (TMS) protocol offers a unique opportunity to explore inhibitory and facilitatory circuitry of the human motor cortex (20). When a subthreshold conditioning pulse (S1) and a suprathreshold test pulse (S2) are applied to the motor cortex through the same coil, the test response is inhibited at interstimulus intervals (ISIs) between 1 and 5 ms (short-interval intracortical inhibition, SICI), while it is facilitated at ISIs of 6–30 ms (intracortical facilitation, ICF); it has been shown that phenomena underlying the generation of ICF and SICI occur at cortical level (21–23), acting differently during execution or suppression of voluntary movements (24,25).
MATERIALS AND METHODS Subjects Ten healthy volunteers (four women and six men, mean age ± SD: 26.5 ± 4.4 years) with no history of neurological disorders were enrolled in the study. No subject was taking medications at the time of, or one month before, the inclusion in the study, and they all had suspended alcohol or caffeine consumption at least 48 hours before. Written informed consent was obtained from all subjects prior to inclusion in the study. Experiments were approved by the local ethical committee and followed the Declaration of Helsinki.
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Transcranial Magnetic Stimulation A Magstim super rapid transcranial magnetic stimulator (2.2 T maximum field output; Magstim Company, Dyfed, UK), connected to either a standard flat coil (outer diameter 12.5 cm) or an eightshaped focal coil (wing diameters of 70 mm), was used. cSP duration was assessed following single pulse stimulation of contralateral motor cortex delivered by the flat coil; the coil was kept in a constant position centered over the vertex for both upper and lower limb; for the upper limb, one edge of the coil was slightly tilted toward the hemisphere to be stimulated. We calculated the mean cSP duration based on trial-by-trial measurements of the cSP duration (five trials per muscle). cSP following each TMS pulse given at 150% of the resting motor threshold (RMT) was determined while subjects activated FDI or TA muscle at approximately 50% of the maximum voluntary contraction, monitored by an isometric dynamometer (26). RMT was defined as the minimum stimulator output that induces motor-evoked potentials (MEPs) of more than 50 μV in at least 5 out of 10 trials when FDI or TA muscle was completely relaxed (27). In each trial, the cSP is measured as the time elapsing from the onset of the MEP until the recurrence of voluntary tonic EMG activity (28). However, voluntary EMG activity does not recover abruptly, but gradually, and a silent period with a biphasic appearance may sometimes be recorded. To avoid both inconveniences, we assumed that if the EMG activity reaches or exceeds the pre-TMS baseline level and lasts for at least 50 ms, reoccurring EMG activity marks the end of the cSP (28). As concerns paired-pulse TMS, we adopted the original protocol proposed by Kujirai and colleagues (21). ICF and SICI were obtained at rest with a subthreshold conditioning stimulus (S1) followed by a suprathreshold test stimulus (S2) at ISIs of 10 and 3 ms, respectively. Test stimuli were set at an intensity of 125% RMT. The conditioning stimuli were set at 75% of the RMT, corresponding at about 90% of the active motor threshold (AMT) (29,30). For pairedpulse recordings, full muscle relaxation is fundamental (31) and was ensured by providing the subjects with audiovisual feedback of the raw EMG at high gain (microV). As it has recently been shown that tsDCS affects RMT (16), we readjusted both test and conditioning stimuli after spinal polarization. For FDI muscle, the handle of the eight-shaped focal coil pointed backwards and rotated about 45° to the mid-sagittal line. The induced current was perpendicular to the central sulcus in the PA direction and was optimal to activate the corticospinal neurons trans-synaptically. The optimal coil position to evoke a reliable MEP, from FDI and TA muscles, was marked on the scalp to ensure identical placement of the coil throughout the experiments.
tsDCS With participants lying supine on a comfortable couch, tsDCS (2.5 mA, 20 min) was delivered by a constant current programmable electrical stimulator (HDCStim, Newronika, Milan, Italy) connected to a pair of rectangular electrodes, one on the thoracic spinal cord (over the spinous process of the tenth thoracic vertebra, from 9th to 11th vertebra, with the major axis parallel to spinal cord) and the other above the right shoulder (1,7). tsDCS electrodes were thick
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Recordings Electromyographic (EMG) recordings were made by two standard nonpolarizable Ag/AgCl surface electrodes (diameter 9 mm; Technomed Europe © 2013, AE Maastricht-Airport, the Netherlands), one placed over the belly of the contralateral first digital interosseus (FDI) muscle, and the other on the skin overlying the
first metacarpophalangeal joint of the first finger of the left hand; for lower limbs, MEPs were recorded through one electrode placed over the belly of the tibialis anterior (TA) muscle and the other over its distal tendon.
BOCCI ET AL. (6 mm) rectangular pieces of saline-soaked synthetic sponge (7 × 5 cm, 35 cm2). We applied current at a density of 0.071 mA/cm2, below the threshold values for tissue damage (32,33). The wide electrode surface avoided the possible harmful effects of highcurrent density. Apart from occasional and short-lasting tingling sensation below the electrodes, tsDCS remained below the conscious sensory threshold throughout the experimental session. tsDCS polarity (sham, cathodal, or anodal) refers to the electrode over the spinal cord. For a sham tDCS, the current was turned on only for 5 sec at the beginning of the sham session and then it was turned off in a ramp-shaped fashion, which induces initial skin sensations indistinguishable from real tDCS. At experimental debriefing, subjects were not able to discriminate between the applied anodal, cathodal, and sham tDCS.
Experimental Design Subjects were studied before and after sham, anodal cathodal tsDCS. Different sessions on the same volunteer were separated by at least one week to avoid possible carry-over effects, and the order of interventional protocols was randomized and balanced across subjects. The subjects were blinded about tsDCS polarity. cSP, SICI, and short intracortical facilitation (SICF) were assessed before tsDCS (T0), immediately after (T1), and at 60 min after tsDCS offset (T2). For all the electrophysiological recordings, we chose the left side to avoid interference from the reference placed over the contralateral shoulder.
Statistical Analysis Values are reported as mean ± 1 standard deviation (SD). MEP amplitudes were measured peak to peak. The MEP amplitudes evoked by paired-pulse stimulation were expressed as a percentage
of the mean MEP amplitude of test stimulus (S2) alone (34,35). As a preliminary evaluation to prove the reliability of our data, raw values at baseline were compared among different sessions (one-way repeated measure analysis of variance [ANOVA], STATISTICA 5.5, StatSoft Inc., Tulsa, OK, USA). The tsDCS-induced changes in each variable were then tested with a two-way repeated measure ANOVA with main factors “stimulation,” three levels (sham, anodal, and cathodal), and “time,” three levels (T0, T1, and T2). The Greenhouse–Geisser ε correction for nonsphericity was applied when necessary. After Bonferroni correction, significance level was set at p < 0.007.
RESULTS Raw data ± 1 SD are summarized in Table 1 (for recordings made from FDI) and in Table 2 (TA muscle). Cortical Silent Period Values at baseline ranged from 162.2 to 232.1 ms and from 141.8 to 215.5 ms, for FDI and TA muscles, respectively, in line with those previously reported in literature (36), and did not differ among experimental conditions (p > 0.3). tsDCS did not modify cSP duration (FDI: F(4, 81) = 0.18, p = 0.9; TA: F(4, 81) = 0.1, p = 0.9, “stimulation × time” interaction). When compared with sham stimulation, neither anodal (FDI: F(2, 54) = 0.37, p = 0.69; TA: F(2, 54) = 0.11, p = 0.87) or cathodal polarization (FDI: F(2, 54) = 0.19, p = 0.83; TA: F(2, 54) = 0.45, p = 0.51) induced significant changes (Fig. 1). Paired-Pulse TMS As for cSP, spinal polarization left ICF unchanged over time (FDI: F(4, 81) = 0.41, p = 0.81; TA: F(4, 81) = 1.18, p = 0.33, “stimulation × time”
Table 1. Row Data Recorded From FDI Muscle (Expressed as Mean Value ± 1 Standard Deviation [SD]). First digital interosseus (FDI) cSP (ms)
Mean SD Mean SD Mean SD
SICI (% of S2 alone) ICF (% of S2 alone)
aT0
aT1
aT2
cT0
cT1
cT2
shT0
shT1
shT2
199.7 37.7 50.2 12.1 123.1 11.8
197.6 32.9 30.2 7.9 122.7 11.2
205.0 29.8 29.9 8.1 120.3 12.6
198.0 37.1 50.7 9.5 122.6 8.7
199.5 44.9 107.2 14.3 120.8 11.8
203.1 34.5 103.3 17.2 126.1 7.8
199.5 31.3 51.8 10.5 119.1 12.3
208.3 30.6 50.4 11.5 122.9 9.1
198.3 29.7 53.1 10.4 116.3 10.2
MEP amplitudes for ISI set at 3 (SICI) and 10 ms (ICF) are expressed as percentage of test stimulus (S2) alone (a = anodal stimulation; c = cathodal stimulation; sh = sham condition). cSP, cortical silent period; ICF, intracortical facilitation; SICI, short intracortical inhibition.
Table 2. Row Data Recorded From TA Muscle (Expressed as Mean Value ± 1 Standard Deviation [SD]). Tibialis anterior (TA) cSP (ms) SICI (% of S2 alone) ICF (% of S2 alone)
Mean SD Mean SD Mean SD
aT0
aT1
aT2
cT0
cT1
cT2
shT0
shT1
shT2
178.4 36.9 50.9 6.9 121.8 9.0
174.5 30.6 32.1 6.5 123.7 9.8
179.2 32.9 29.9 6.1 118.6 9.7
183.2 34.8 52.2 14.9 118.9 6.7
185.0 29.7 94.5 13.4 123.5 5.7
180.7 35.1 98.7 15.8 127.1 8.7
172.5 52.7 53.3 8.5 119.2 8.2
180.0 57.0 53.8 9.3 119.6 8.8
174.0 42.5 55.7 14.1 120.0 10.1
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MEP amplitudes for ISI set at 3 (SICI) and 10 ms (ICF) are expressed as percentage of test stimulus (S2) alone (a = anodal stimulation; c = cathodal stimulation; sh = sham condition). cSP, cortical silent period; ICF, intracortical facilitation; SICI, short intracortical inhibition.
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tsDCS AND INTRACORTICAL EXCITABILITY
Figure 1. Cortical silent period (cSP). tsDCS left cSP duration unchanged over time, when recordings were made from (a) FDI or (b) TA muscle. On the right: representative traces recorded from TA muscle in the same subject showing no modification between anodal and cathodal stimulation. FDI, first digital interosseus; TA, tibialis anterior; tsDCS, transcutaneous spinal direct current stimulation.
Figure 2. Intracortical facilitation (ICF). As for cSP, tsDCS left MEPs amplitude unchanged when stimuli were administered at ISI = 10 ms (data are expressed as percentage of the mean MEP amplitude elicited by test stimulus, S2, alone). Representative traces (right), recorded from TA muscle, show no modification at T1 and T2, following either anodal or cathodal polarization, compared with the facilitated MEP at T0. The MEP obtained following the test stimulus (S2) alone was shown at the top. cSP, cortical silent period; MEP, motor-evoked potential; tsDCS, transcutaneous spinal direct current stimulation.
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obtained by paired-pulse stimulation at ISI = 10 ms. This trend was confirmed at each time point, both for FDI and TA muscle (p > 0.3). Conversely, tsDCS significantly changed MEP amplitudes at ISI of 3 ms (Fig. 3), recorded both by FDI (F(4,81) = 36.9, p < 0.0001,
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interaction: Fig. 2); in particular, when compared with sham condition, neither anodal (FDI: F(2, 54) = 0.21, p = 0.81; TA: F(2, 54) = 0.3, p = 0.74) or cathodal polarization (FDI: F(2, 54) = 1.73, p = 0.19; TA: F(2, 54) = 1.05, p = 0.36) significantly modified MEP amplitudes
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Figure 3. Short intracortical inhibition (SICI). Cathodal tsDCS significantly improved MEPs amplitude at ISI = 3 ms, while anodal one elicited opposite effects (data are expressed as percentage of the mean MEP amplitude elicited by test stimulus alone). Representative traces (on the top) were recorded in the same subject from FDI (left) and TA (right) muscles; for each muscle and polarity, the MEP obtained following the test stimulus (S2) alone was also shown. *p < 0.05; **p < 0.01. FDI, first digital interosseus; MEP, motor-evoked potential; TA, tibialis anterior; tsDCS, transcutaneous spinal direct current stimulation.
“stimulation × time” interaction) and TA muscle (F(4,81) = 25.0, p < 0.0001). When analyzed separately, cathodal tsDCS improved MEP size compared with sham condition (FDI: F(2,54) = 31.9, p < 0.0001; TA: F(2,54) = 15.9, p < 0.0001), while anodal one elicited opposite changes (vs. sham: F(2,54) = 6.56, p = 0.0028; F(2,54) = 8.6, p = 0.0006 for FDI and TA muscles, respectively; vs. cathodal: F(2,54) = 64.5, p < 0.0001; F(2,54) = 46.9, p < 0.0001). The effects remained stable at T1 and T2 for both cathodal (FDI: T1 vs. T0: p < 0.0001, T2 vs. T0: p < 0.0001; TA: T1 vs. T0: p < 0.0001, T2 vs. T0: p < 0.0001) and anodal polarization (FDI: T1 vs. T0: p = 0.0087, T2 vs. T0: p = 0.0076; TA: T1 vs. T0: p = 0.012, T2 vs. T0: p = 0.011).
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The main finding of our work is that tsDCS is able to modulate intracortical excitability in a polarity specific manner. In particular, modifications of SICI without interfering with cSP and ICF prompt a specific modulation of inhibitory GABA(A)ergic drive within primary motor cortex. While SICI is likely to be mediated by GABA(A) receptors (37–39), ICF hinges on glutamatergic pathways (40,41), although a more complex interaction between inhibitory and excitatory circuits has been suggested for its generation (22,42,43); conversely, cSP mainly reflects postsynaptic GABA(B)ergic function, with spinal mechanisms partially contributing to the early part of EMG inhibition (42,44,45). Previous studies have reported a significant effect of tsDCS both on postactivation depression and recruitment curve of www.neuromodulationjournal.com
H-reflex (8,9); although modulation of segmental circuits is likely associated with supraspinal intracortical excitability changes, whether and how these modifications take place are still a matter of debate. In particular, tsDCS may have polarity-specific effects on spinal pathways different from those induced on supraspinal targets. The intriguing possibility to modulate the functional state of the brain by influencing spinal drive was previously suggested by works using invasive spinal cord stimulation (SCS). In particular, SCS was demonstrated to be effective in restoring locomotion in animal models of Parkinson’s disease, paralleled by a disruption of antikinetic low-frequency synchronous corticostriatal oscillations (46,47). In humans, it is known that alternating currents epidurally delivered to the posterior columns of the spinal cord are able to deeply modify sensory processing at thalamic relays and cortical levels (48). More importantly, possible support for a cortical mechanism in humans comes from a recent report where SCS seems to enhance the intracortical facilitation in patients with neuropathic pain (49). However, SCS is a useful tool different from tsDCS, using, for instance, intensities above perceptive threshold; moreover, its mechanisms of action are better understood, ranging from spinal and supraspinal targets to hemodynamic changes (50,51). Here, different from SCS, noninvasive spinal stimulation seems to specifically interfere with cortical inhibitory networks, not with facilitatory processing. In this scenario, the mechanisms by which tsDCS could modulate cortical activities, especially for upper limb muscles, remain elusive.
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tsDCS AND INTRACORTICAL EXCITABILITY In fact, while dorsal tsDCS is likely to affect both descending and ascending pathways to TA, it does not directly alter target pathways to and from FDI muscle. Possible explanation comes from spinal injuries studies, describing an increased cortical representation of nonimpaired upper limb muscles in paraplegic patients (52). This is also in line with TMS investigations in paraplegics showing an increased representation of preserved muscles proximal to the lesion level (53). Specifically, expansion of motor maps into the deafferented cortex is commonly attributed both to unmasking of the latent intracortical connections between hemispheres and to activity-dependent changes underlying the so-called long-term potentiation (LTP) (54–56). Along this view, Topka and colleagues reported that TMS activated a large fraction of motorneuron pools and evoked MEPs with shorter latencies from a large number of scalp positions in abdominal muscles rostral to the level of SCI (57). Others suggested that SCI is also associated with a high degree of synergic co-activation of muscles proximal to the lesion level (58). Lack of intracortical GABA(A)ergic inhibition may favor, at least in part, all these changes. From a molecular point of view and by analogy with animal models, we could speculate that the effects of invasive spinal polarization could be induced by the modulation of indirect spinal projections to noradrenergic locus coeruleus (LC) neurons, which has widespread projections to the neocortical brain (59–62). Alternatively, a critical role in brain plasticity could be played by a dynamic modulation of serotonergic ascending pathways, especially through parallel and partially overlapping projections arising from the median and dorsal raphe nuclei (63–66). Although not directly investigated in the present study, as serotonergic projections seem to participate in the regulation of different functional systems (motor, somatosensory, limbic), tsDCS may ultimately modulate this connectivity.
ways (74). For the calculation of cSP, we adopted one of the two more used and accepted protocols proposed by an ad hoc committee of the International Federation of Clinical Neurophysiology (IFCN) (28), although some excellent papers have recently described alternative methods to improve accuracy for the cSP estimation (75); however, these methods are not standardized yet and require devices and software for data analysis not available in many laboratories. Finally, lack of intracortical effects, following tsDCS, has been recently reported elsewhere (16); the results, however, can difficultly be compared with ours because they studied a different anatomical region, with a different recording montage and stimulation intensities.
CONCLUSIONS The tsDCS could be of particular interest as a noninvasive, safe, promising therapeutic tool in managing a number of human diseases. This technique could be useful especially as an early rehabilitation strategy in patients with acute brain lesions, when other noninvasive brain stimulation (NIBS) tools are not indicated due to safety concerns, or even in the treatment of neurological disorders characterized by abnormal interhemispheric processing. In addition, the possibility to modulate supraspinal and intracortical processing of motor inputs makes tsDCS a useful approach, complementary to either SCS or NIBS techniques, to modify spinal drive through nonspinal mechanisms. Our results prompt further investigations, especially in patients with spinal cord injuries, brain diseases, or pain syndromes.
Acknowledgements
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We gratefully acknowledge the participation of all subjects, as well as Mr. C. Orsini and Ms. L. Parenti for their excellent technical assistance. We also thank Prof. M. Caleo at Scuola Normale Superiore, Pisa, for his support in language editing. The paper was supported in part by the Italian operating and development MIUR PRIN grant year 2006, n. 2006062332_002.
Authorship Statement Tommaso Bocci designed the study, collected the data and assisted in writing the manuscript. Davide Barloscio participated in subject recruitment, data collection and assisted in writing the manuscript. Maurizio Vergari assisted with data analysis and writing the manuscript. Andrea Di Rollo assisted with subject recruitment and writing the manuscript. Simone Rossi and Alberto Prioro helped design the study. Ferdinando Sartucci assisted in study design and writing of the manuscript.
How to Cite this Article: Bocci T., Barloscio D., Vergari M., Di Rollo A., Rossi S., Priori A., Sartucci F. 2015. Spinal Direct Current Stimulation Modulates Short Intracortical Inhibition. Neuromodulation 2015; 18: 686–693
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Methodological Issues and Possible Pitfalls From the beginning, our group has adopted the montage we used here, with the active electrode placed over the lower thoracic spinal cord and the return one over the right arm. Although different settings and stimulation parameters have been proposed (10,16), the “monopolar” montage dampens the spread of the current toward the higher spinal cord levels or to the brainstem, reducing at the same time interference between anodal and cathodal effects and decreasing cutaneous shunt (67). Equally important, longitudinal electrical fields, as those induced by this montage, are known to have potential implications for rehabilitation, as they both promote axonal regrowth and prevent fiber degeneration (68). Our study has some limitations. First, we did not assess the possibility to interfere with presynaptic GABA(B)ergic interneurons, likely involved in a late period of disinhibition, as their activity could be evaluated only by using a complex triple-stimulation paradigm (69). Second, we cannot exclude an influence of SICF on SICI, although this contamination occurs only at discrete intervals typically sparing the ISI of 3 ms and with stimulus intensities higher than those we used here (ISI ∼4.5 ms and S1 intensity >90% AMT) (70–72). Anywhere, SICF and SICI are strictly related each other and their effects converge on pyramidal neurons to elicit MEPs (73); altogether, we cannot easily rule out a modulation of both facilitatory and inhibitory intracortical pathways. Third, as cSP is also due to spinal mechanisms comprising motorneuron hyperpolarization and activation of inhibitory Renshaw network, it partly represents an indirect measure of the integrity of GABA(b)ergic intracortical path-
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