J Neurophysiol 105: 2802–2810, 2011.

First published March 23, 2011; doi:10.1152/jn.00617.2010.

Transcranial direct current stimulation effects on I-wave activity in humans

Nicolas Lang,1 Michael A. Nitsche,2 Michele Dileone,3 Paolo Mazzone,4 Javier De Andrés-Arés,5
Luis Diaz-Jara,5 Walter Paulus,2 Vincenzo Di Lazzaro,3 and Antonio Oliviero6
1
Department of Neurology, Christian-Albrechts University, Kiel; and 2Department of Clinical Neurophysiology, Georg-August
University, Göttingen, Germany; 3Institute of Neurology, Università Cattolica and 4Neurochirurgia CTO, Rome, Italy; and
5
Unidad de Dolor, Hospital Virgen de la Salud and 6FENNSI, Hospital Nacional de Paraplejicos, SESCAM, Toledo, Spain
Submitted 12 July 2010; accepted in final form 23 March 2011

Lang N, Nitsche MA, Dileone M, Mazzone P, De Andrés-Arés al. 2004; Nitsche and Paulus 2001; Nitsche et al. 2003a).
J, Diaz-Jara L, Paulus W, Di Lazzaro V, Oliviero A. Transcranial Pharmacological investigations in humans have shown that
direct current stimulation effects on I-wave activity in humans. J

Downloaded from http://jn.physiology.org/ by 10.220.33.5 on September 25, 2017

tDCS aftereffects are affected by drugs that change neuronal
Neurophysiol 105: 2802–2810, 2011. First published March 23, 2011;
doi:10.1152/jn.00617.2010.—Transcranial direct current stimulation membrane excitability or N-methyl-D-aspartate (NMDA) re-
(tDCS) of the human cerebral cortex modulates cortical excitability ceptor efficacy (Liebetanz et al. 2002; Nitsche et al. 2003b).
noninvasively in a polarity-specific manner: anodal tDCS leads to This is compatible with the notion that activity-dependent
lasting facilitation and cathodal tDCS to inhibition of motor cortex synaptic plasticity, such as long-term potentiation (LTP) and
excitability. To further elucidate the underlying physiological mech- long-term depression (LTD), shares some similarities with the
anisms, we recorded corticospinal volleys evoked by single-pulse effects induced by tDCS. Conflicting results have been ob-
transcranial magnetic stimulation of the primary motor cortex before
tained on the question of whether MEPs elicited by transcranial
and after a 5-min period of anodal or cathodal tDCS in eight conscious
patients who had electrodes implanted in the cervical epidural space electric stimulation are affected by tDCS or not (Ardolino et al.
for the control of pain. The effects of anodal tDCS were evaluated in 2005; Nitsche and Paulus 2001; Nitsche et al. 2003a), leaving
six subjects and the effects of cathodal tDCS in five subjects. Three the issue of whether tDCS-induced aftereffects are localized
subjects were studied with both polarities. Anodal tDCS increased the primarily intracortically unresolved. Imaging has shown that
excitability of cortical circuits generating I waves in the corticospinal tDCS of primary motor cortex can provoke sustained and
system, including the earliest wave (I1 wave), whereas cathodal tDCS widespread changes in regional neuronal activity of the brain
suppressed later I waves. The motor evoked potential (MEP) ampli- (Lang et al. 2005). Additionally, there is evidence that effects
tude changes immediately following tDCS periods were in agreement on primary motor cortices are more pronounced in the stimu-
with the effects produced on intracortical circuitry. The results deliver
lated hemisphere and affect not only corticospinal circuits
additional evidence that tDCS changes the excitability of cortical
neurons. involved in producing MEPs but also inhibitory interneurons
mediating transcallosal inhibition from the contralateral hemi-
corticospinal volleys; transcranial magnetic stimulation; repetitive sphere (Lang et al. 2004). TMS research suggests that the
transcranial magnetic stimulation; theta-burst stimulation; paired as- effects of tDCS on corticospinal excitability during a short
sociative stimulation period of stimulation primarily depend on subthreshold resting
membrane potential changes, but the longer-lasting aftereffects
NEURONAL EXCITABILITY in the brain can be modified by appli-
are due to shifts in intracortical inhibition and facilitation,
cation of direct current (DC). Surface-positive polarization of which are mediated synaptically (Nitsche et al. 2005). How-
rat and cat cerebral cortex raises mean firing rates of neurons ever, the precise physiological mechanisms of the aftereffects
recorded in deep cortical layers, whereas surface-negative induced by tDCS still remain unclear.
polarization reduces spontaneous firing (Bindman et al. 1962, Considering the growing therapeutic potential of tDCS,
1964; Creutzfeldt et al. 1962; Purpura and McMurtry 1965). If further knowledge about the underlying mechanisms and the
DC is continuously applied for 5 min or more, it can provoke origin of its effects is needed. One methodological approach to
sustained changes in neuronal firing rates that last for many address this problem is the recording of corticospinal volleys
hours after the current is switched off (Bindman et al. 1962). evoked by TMS (Di Lazzaro et al. 2004). Since the synchro-
In humans, transcranial DC stimulation (tDCS) of the pri- nous neural volleys are a direct measure of the effectiveness of
mary motor cortex modulates corticospinal excitability in a synaptic inputs to corticospinal neurons, the ability to record
polarity-specific manner when assessed by transcranial mag- descending corticospinal activity in conscious humans has
netic stimulation (TMS): motor evoked potentials (MEPs) in provided useful insight into the aftereffects of different brain
contralateral hand muscles are facilitated by anodal tDCS and stimulation techniques (Di Lazzaro et al. 1998c, 2005).
suppressed by cathodal tDCS of the primary motor cortex In the present study we recorded corticospinal activity
(Nitsche and Paulus 2000). Consistent with animal data, these evoked by single-pulse TMS before and after 5 min of anodal
changes in excitability persist beyond the time of stimulation if and cathodal tDCS of primary motor cortex in eight conscious
tDCS is given for several minutes and can remain stable for an subjects, without abnormalities of the brain or the cervical
hour or more if tDCS is applied for 9 min or longer (Lang et spinal cord, who had cervical spinal electrodes implanted
chronically for control of pain. It should be considered that
Address for reprint requests and other correspondence: A. Oliviero, Hospital
these patients are rare and that they are available only for a
Nacional de Paraplejicos, FENNSI Group, Finca La Peraleda s/n, 45071, short period of time; thus only a restricted number of record-
Toledo, Spain (e-mail: [email protected]). ings could be performed. Since a longer duration of stimulation
2802 0022-3077/11 Copyright © 2011 the American Physiological Society www.jn.org
 I-WAVE MODULATION BY tDCS 2803

seems not to result in qualitatively different tDCS effects Transcranial magnetic stimulation. Magnetic stimulation was per-
(Nitsche et al. 2005), we used a relatively short tDCS to be able formed with a Medtronic Magpro X100 (Medtronic Functional Diag-
to cover the whole time course of the effects. The aim of the nostics, Skovlunde, Denmark) in subject 1 and with a high-power
experiments was to learn more about the origin of tDCS- Magstim 200 (Magstim, Whitland, UK) in subjects 2– 8. A figure-of-
induced aftereffects on cortical excitability and to enable com- eight coil (with external loop diameters of 7 cm for Medtronic and 9
parisons with other noninvasive brain stimulation techniques cm for Magstim) was held over the right motor cortex at the optimum
on a physiological basis. scalp position to elicit motor responses in the contralateral FDI.
Stimuli used were monophasic for both stimulators. Intensities are
MATERIALS AND METHODS expressed as percentage of the maximum stimulator output. Resting
motor threshold (RMT) was defined according to the recommenda-
Patients. As described previously (Di Lazzaro et al. 1998c), we
tions of the International Federation of Clinical Neurophysiology
recorded descending corticospinal activity evoked by TMS of the
primary motor cortex directly from the high cervical epidural space of (IFCN) Committee (Rothwell et al. 1999) as the minimum stimulus
eight conscious patients (4 men, 4 women; mean age 41 ⫾ 9 yr). intensity that produced a reliable MEP (⬎50 ␮V in 50% of 10 trials)
These patients had no abnormalities of the central nervous system at with the tested muscle at rest. RMT was obtained with a 1% step-by-
brain and cervical spinal cord levels (subjects 4 and 5 were paraplegic step searching approach.
Two different orientations of the stimulating coil over primary

Downloaded from http://jn.physiology.org/ by 10.220.33.5 on September 25, 2017

with spinal cord lesion at thoraco-lumbar levels) and had electrodes
inserted for control of intractable pain. All patients gave their written motor cortex were used, with the induced current flowing either in a
informed consent. All subjects were right-handed. The study was latero-medial (LM) or in a posterior-anterior (PA) direction. RMT was
performed according to the Declaration of Helsinki and was approved determined separately for LM and PA stimulation. The researcher
by the ethics committees of the Hospital Nacional de Paraplejicos, performing TMS was not blinded about tDCS conditions (anodal or
Toledo (subjects 1–3, 5, and 7) and the Medical Faculty of Università cathodal).
Cattolica, Rome (subjects 4, 6, and 8). Demographic data and phar- D and I1 wave identification. LM magnetic stimulation was used to
macological treatment are reported in Table 1. identify the latency of the earliest (D wave) descending volley (Di
We evaluated the effects of anodal tDCS in subjects 1–5 and 8 and Lazzaro et al. 2004). The responses to 20 stimuli at an intensity of
of cathodal tDCS in subjects 4 – 8 (i.e., subjects 4, 5, and 8 were 150% RMT were averaged at rest with LM magnetic stimulation. In
studied with both tDCS polarities). When both anodal and cathodal four subjects (subjects 2, 3, 5, and 8) it was not possible to evoke a
tDCS were tested, the two experiments were separated at least by 24 clear D wave by using LM magnetic stimulation, and we used a
h. Subjects 4 and 8 received anodal tDCS before cathodal tDCS, while different approach to identify the D and I1 waves. The amplitude of
subject 5 received cathodal tDCS first. Patients were blinded about the first wave evoked by PA magnetic stimulation (I1 wave) is
tDCS conditions (anodal or cathodal). increased during voluntary contraction of the target muscles (Di
Transcranial direct current stimulation. tDCS was applied by a Lazzaro et al. 1998b), while the D wave is unchanged (Di Lazzaro et
battery-driven constant-current stimulator (Schneider Electronic, al. 1999b). In the four subjects without a clear D wave evoked by LM
Gleichen, Germany) via conductive rubber electrodes, placed in two magnetic stimulation, we evaluated the effects of voluntary contrac-
saline-soaked sponges (5 ⫻ 7 cm), with one electrode positioned over tion on the first wave evoked by PA TMS.
the optimal cortical representation of the left first dorsal interosseus Moreover, to better discern (between D and I waves) the descend-
muscle (FDI), as revealed by TMS, and the other electrode above the ing waves, the latencies of the earliest potentials evoked by magnetic
contralateral orbit. This montage has been shown to be most effective stimulation in these patients were compared with the mean values of
in modulating corticospinal excitability of primary motor cortex the earliest potentials evoked by electrical anodal stimulation in 10
(Nitsche and Paulus 2000). DC polarity refers to the electrode over the patients with a high cervical epidural electrode who had previously
right primary motor cortex. In all patients tDCS was given with an been studied (Di Lazzaro et al. 2005). In those individuals, electrical
intensity of 1 mA for 5 min. The current was ramped up or down over anodal stimulation evoked the shortest-latency potential, with a mean
the first and last 5 s of stimulation, respectively, in order to avoid latency of 2.6 ⫾ 0.1 ms and a range of 2.4 –2.8 ms.
alternating current (AC) current transients causing neuronal firing Evaluation of tDCS effects on corticospinal volleys. To evaluate the
(Nitsche et al. 2008). During DC stimulation constant-current output effects of anodal tDCS, the responses to 20 stimuli at an intensity of
was monitored by a built-in ampere meter. 110% RMT and 130% RMT were averaged at rest with PA magnetic
Because of the time limitations of studying epidural implanted stimulation (130% RMT was recorded to be sure that no waves were
patients we decided to use 5 min of tDCS, because this duration has saturated). To evaluate the effects of cathodal tDCS, the responses to
been demonstrated to be effective and the effects are short enough to 20 stimuli at an intensity of 150% RMT were averaged at rest with PA
guarantee a baseline return within 20 –30 min (Nitsche et al. 2005). magnetic stimulation. We used different TMS stimulation intensities
Table 1. Demographic and pharmacological data
Subject Age, yr Sex Weight, kg Pharmacological Treatment

1 27 F 70 Paroxetine (20 mg/day)†

Gabapentin (600 mg/day)†
Tramadol (150 mg/day)†
2 43 F 64 Carbamazepine (600 mg/day)†
Gabapentin (1,200 mg/day)†
3 49 M 78 Pregabalin (200 mg/day)*
4‡ 32 M 75 No drugs
5‡ 42 M 80 Paracetamol (2,000 mg/day)*
6 44 M 78 No drugs
7 40 F 65 No drugs
8 54 M 76 Pregabalin (200 mg/day)*
Mean 41 ⫾ 9 73 ⫾ 6

*Drugs were suspended 24 h before the study. †Drugs were suspended 48 h before the study. ‡Spinal cord injury (thoraco-lumbar level).

J Neurophysiol • VOL 105 • JUNE 2011 • www.jn.org

2804 I-WAVE MODULATION BY tDCS

for evaluation of anodal and cathodal stimulation to optimize the correction for multiple comparisons. For anodal tDCS, a P value of
evaluation after tDCS. For anodal stimulation we needed an intensity ⬍0.0125 (⫽ 0.05/4) was considered significant. For cathodal tDCS, a
that did not saturate the I-wave generation to avoid a ceiling effect. In P value of ⬍0.01 (⫽ 0.05/5) was considered significant. To confirm
contrast, for cathodal stimulation we needed an intensity that opti- the consistency of the statistical analysis for parametric data, we also
mized the possibility of recording a reduction of the number and performed a repeated-measures analysis for nonparametric data using
amplitude of I waves. To evaluate the time course of the effects of the Friedman test. For this latter analysis we used the raw, not
tDCS on MEP amplitudes, the intensity of the TMS (110% RMT for normalized, data.
anodal and 150% RMT for cathodal stimulation) was kept constant Unless otherwise stated, data are presented as means ⫾ SD.
before and after the application of tDCS.
Data acquisition. Recordings were made simultaneously from the
epidural electrode and from the relaxed FDI of the left hand. MEPs RESULTS
and corticospinal volleys were amplified and filtered (bandwidth 3 None of the patients experienced any adverse effects during
Hz–3 kHz) by D360 amplifiers (Digitimer, Welwyn Garden City, or after the experiments.
UK). Data were sampled at 10 kHz, collected on a computer, and Mean baseline RMT was 54.4 ⫾ 4.4% of maximum stimu-
stored for later analysis with a CED 1401 A/D converter (Cambridge lator output. LM magnetic stimulation evoked the earliest
Electronic Design, Cambridge, UK).
negative potential in four of the eight patients. It had a latency

Downloaded from http://jn.physiology.org/ by 10.220.33.5 on September 25, 2017

Epidural recordings were made between the most proximal and
distal of the four electrode contacts of the epidural electrode. These of 2.4 ms in subject 1, 2.6 ms in subjects 6 and 7, and 2.9 ms
had a surface area of 2.54 mm2 and were 30 mm apart. The distal in subject 4. The short latency of this wave is consistent with
contact was connected to the reference input of the amplifier. Ampli- direct activation of corticospinal axons; we therefore defined
tude of the volleys was measured from onset to peak: onset was this volley as D wave (Di Lazzaro et al. 2004). These earliest
defined either as the immediately preceding trough or as the initial potentials evoked by LM magnetic stimulation in these patients
deflection from baseline (Di Lazzaro et al. 2005). were compared with the mean values of the earliest potentials
Subjects 2, 3, 5, and 8 had no clear D wave evoked by LM magnetic evoked by electrical anodal stimulation in 10 patients with a
stimulation; therefore we identified the I1 wave with a different high cervical epidural electrode who had previously been
approach. The I1 wave is known to be sensitive to cortical excitability studied (Di Lazzaro et al. 2005). In those individuals, electrical
changes produced by voluntary contraction of the target muscle, while
anodal stimulation evoked the shortest-latency potential, with a
the D wave is not (Di Lazzaro et al. 1998b, 1999b). If the amplitude
of the first (clear) wave evoked by PA magnetic stimulation was mean latency of 2.6 ⫾ 0.1 (SD) ms with a range between 2.4
increased during voluntary contraction of the left FDI (voluntary and 2.8 ms. The latency of this potential was similar to that of
contraction of ⬃50% of maximum), we considered this wave an I1 the earliest potential evoked by LM magnetic stimulation in the
wave. present study, consistent with our assumption that it was a D
We compared the corticospinal volleys and FDI motor responses wave. In these subjects, PA magnetic stimulation evoked a
evoked by a standard TMS pulse before and after tDCS. For anodal series of descending waves; the first of these waves had a
stimulation, we averaged the responses to 20 PA magnetic stimuli at latency that was 1.1–1.4 ms longer than the earlier volley
an intensity of 110% RMT delivered immediately before anodal tDCS recruited by LM magnetic stimulation. Since the earliest volley
and to 4 sets of 20 stimuli delivered after the end of anodal tDCS elicited by LM magnetic stimulation was thought to be a D
(each set lasting for ⬃2 min). In subjects 2, 4, 5, and 8, we recorded
wave, we defined the later volleys recruited by PA magnetic
an additional set of 20 stimuli 8 min after anodal tDCS. In subjects 2
and 3 we also repeated epidural recording 20 min after the end of stimulation as I waves, numbered in order of their appearance.
tDCS. For cathodal stimulation, we averaged the responses to 20 PA Subjects 2, 3, 5, and 8 had no clear D wave evoked by LM
magnetic stimuli at an intensity of 150% RMT delivered immediately magnetic stimulation; therefore, we identified the I1 wave by
before cathodal tDCS and to 5 sets of 20 stimuli delivered after the an approach with voluntary muscle contraction (Di Lazzaro et
end of cathodal tDCS (each set lasting ⬃2 min). al. 1998b, 1999b). The amplitude of the first wave evoked by
Any (rare) trials contaminated by any kind of artifacts were PA magnetic stimulation was increased during voluntary con-
excluded from the analyses before averaging across trials. traction of the left FDI, so we considered this wave an I1 wave.
Data analyses. For the analysis of the effect of tDCS on cortico- Moreover, in these subjects the I1 wave (identified with the
spinal volleys and MEPs, anodal and cathodal stimulation were method of the sensitivity to voluntary contraction) had a
evaluated separately. We calculated the intraindividual amplitude
latency that was 1.1–1.4 ms longer than the mean latency of D
means of 1) total volleys (the sum of the amplitudes of all I waves),
2) the I1 wave and later waves (the sum of the amplitudes of all the wave obtained in 10 control subjects with anodal electrical
waves following the I1 wave) separately, and 3) MEPs. We discerned stimulation (Di Lazzaro et al. 2005). This is consistent with our
I1 and later I waves because there is evidence that I1 wave and later assumption that it was an I1 wave. In these subjects, PA
I waves have different characteristics and that different neurons are magnetic stimulation evoked a series of descending waves.
involved in their generation (Di Lazzaro et al. 2004). Amplitude data Since the first of these waves most probably represented the I1
were log transformed in order to normalize their spread. Total volley wave, we defined the following volleys recruited by PA mag-
and MEP amplitudes were entered into two separate repeated-measure netic stimulation as later I waves, numbered in order of their
analyses of variance (ANOVAs) incorporating, where necessary, a appearance starting from the I2 wave.
Greenhouse-Geisser correction for nonsphericity. Five time points for Figure 1 shows the measurements at baseline and at two time
anodal stimulation (baseline and 4 blocks of postintervention record-
points after tDCS of two representative subjects (anodal tDCS
ings of 20 stimuli, each ⬃2 min) and six time points for cathodal
stimulation (baseline and 5 blocks of postintervention recordings of of subject 8 and cathodal tDCS of subject 5). Individual data
20 stimuli, each ⬃2 min) were entered into the ANOVAs. I1 wave from all subjects are reported in the supplemental material for
and later volley amplitudes were entered into two separate repeated- this article (Supplemental Figs. S1–S5).1
measure ANOVAs incorporating, where necessary, a Greenhouse-
Geisser correction for nonsphericity. In the case of significant effects, 1
Supplemental Material for this article is available online at the Journal
post hoc analyses with paired t-test were applied with Bonferroni website.

J Neurophysiol • VOL 105 • JUNE 2011 • www.jn.org

 I-WAVE MODULATION BY tDCS 2805

Fig. 1. Corticospinal volleys and motor evoked po-

tentials (MEPs) evoked by magnetic stimulation at
baseline and 2 time points after transcranial direct
current (DC) stimulation (tDCS) (5 min, 1 mA) of 2
representative subjects. Each trace is the average of
20 sweeps. Posterior-anterior (PA) magnetic stimu-
lation evokes a series of descending I waves. The
earliest wave is the I1 wave. Anodal tDCS increased
the amplitude of all I waves including the I1 wave.
MEP amplitude was also increased by anodal tDCS
(subject 8). Cathodal tDCS reduced the amplitude of
the later I waves. MEP amplitude was also reduced
by cathodal tDCS (subject 5).

Downloaded from http://jn.physiology.org/ by 10.220.33.5 on September 25, 2017

Anodal tDCS. MEP and I-wave amplitudes were larger with tDCS application [Spearman test, r2 ⫽ 0.022; P ⫽ not signif-
a TMS stimulus intensity of 130% RMT compared with 110% icant (ns)], but a certain degree toward a linear correlation was
RMT intensity (P ⬍ 0.05, paired t-test), confirming that MEP observed between total volley and MEP amplitude changes
and I-wave amplitude were not saturated with the 110% inten- 2– 4 min after the tDCS application (Spearman test, r2 ⫽ 0.436;
sity, which was the TMS intensity used for the evaluation of P ⫽ ns).
the effects of anodal tDCS. Figure 2, C and D, show the time course of the effect of
Mean I wave and MEP amplitudes are reported in Table 2. anodal tDCS on the amplitudes of the I1 and on later I waves
In Fig. 2 the amplitude ratio is reported (post/baseline). Figure (the sum of the amplitudes of all waves following the I1 wave).
2A shows the time course of the effects of anodal tDCS on the Mean I1-wave amplitude was increased after the end of tDCS.
amplitudes of the total volley (the sum of the amplitudes of all A repeated-measures ANOVA on normalized data showed a
I waves). Mean total volley was increased by ⬃65% relative to significant effect of time (F4,20 ⫽ 3.846, P ⫽ 0.018), and post
baseline values 0 – 4 min after the end of tDCS. A repeated- hoc analysis revealed that I1 amplitudes were significantly
measures ANOVA on normalized data showed a significant increased within the first 2 min after anodal tDCS (P ⫽
effect of time (F4,20 ⫽ 11.546, P ⫽ 0.0001). Post hoc analysis 0.0018). Also, later I-wave amplitudes were increased after the
on total volley showed that total volley amplitudes were end of tDCS. For the later I waves, repeated-measures
significantly increased within the first 4 min after anodal tDCS ANOVA on normalized data showed a significant effect of
(0 –2 min, P ⫽ 0.0005; 2– 4 min, P ⫽ 0.0007). MEPs were time (F4,20 ⫽ 10.620, P ⫽ 0.0002). Post hoc analysis revealed
increased (on average ⬃120% of their pre-tDCS size) imme- that later I-wave amplitudes were significantly increased within
diately after the end of anodal tDCS (F4,20 ⫽ 3.845, P ⫽ 0.018; the first 4 min after anodal tDCS (0 –2 min, P ⫽ 0.0056; 2– 4
Fig. 2B). Post hoc analysis of MEPs showed that MEP ampli- min, P ⫽ 0.0007). Anodal tDCS increased the mean I1 ampli-
tudes were significantly increased within the first 6 min after tude to ⬃40% (0 –2 min) and mean later I-wave amplitude to
anodal tDCS (0 –2 min, P ⫽ 0.0031; 2– 4 min, P ⫽ 0.0007; ⬃80% (0 – 4 min) of the baseline. Subjects 2, 4, 5, and 8 were
4 – 6 min, P ⫽ 0.008). There was no correlation between the studied again 8 min after the end of tDCS. At this time the
total volley and MEP amplitude changes immediately after descending volleys had completely recovered to pre-tDCS
Table 2. Mean I wave and MEP amplitudes
I1 Waves, ␮V Later I Waves, ␮V Total Volley, ␮V MEP, mV

Anodal tDCS (n ⫽ 6)
Baseline 6.9 (2.6) 9.3 (3.8) 16.2 (5.3) 0.92 (0.25)
Post 1 (0–2 min) 9.9 (4.3) 17.0 (6.1) 26.9 (8.6) 1.54 (0.79)
Post 2 (2–4 min) 9.0 (3.0) 16.9 (8.2) 25.9 (10.6) 1.55 (0.71)
Post 3 (4–6 min) 9.1 (3.6) 12.6 (3.8) 21.7 (6.1) 1.47 (0.52)
Post 4 (6–8 min) 8.7 (3.3) 8.6 (4.3) 13.3 (4.7) 1.13 (0.56)
Cathodal tDCS (n ⫽ 5)
Baseline 6.0 (2.2) 19.9 (4.9) 25.9 (5.6) 1.49 (1.12)
Post 1 (0–2 min) 5.2 (1.7) 12.5 (5.6) 17.7 (6.3) 1.22 (0.89)
Post 2 (2–4 min) 4.5 (1.9) 12.0 (3.3) 16.5 (3.5) 1.27 (0.98)
Post 3 (4–6 min) 5.4 (2.9) 16.0 (4.9) 21.4 (7.1) 1.34 (0.93)
Post 4 (6–8 min) 4.6 (2.3) 15.1 (6.7) 19.7 (8.0) 1.38 (0.89)
Post 5 (8–10 min) 6.3 (2.6) 18.3 (7.6) 24.6 (8.3) 1.46 (0.95)

Values are means (SD). MEP, motor evoked potential; tDCS, transcranial direct current stimulation.

J Neurophysiol • VOL 105 • JUNE 2011 • www.jn.org

2806 I-WAVE MODULATION BY tDCS

Fig. 2. Effects of anodal tDCS on the ampli-

tude of I waves and MEPs in individual sub-
jects (dashed lines). The continuous line rep-
resents the grand mean of all subjects. Error
bars indicate SD. A: time course of the effects
of anodal tDCS on the amplitudes of the total
volley (the sum of the amplitudes of all I
waves). Mean total volley was increased after
the end of tDCS. B: time course of the effects
of anodal tDCS on MEP amplitudes. Mean
MEP amplitude were increased after the end
of tDCS. C: time course of the effect of anodal
tDCS on the amplitudes of the I1 waves.
Mean I1-wave amplitude was increased after

Downloaded from http://jn.physiology.org/ by 10.220.33.5 on September 25, 2017

the end of tDCS. D: time course of the effect
of anodal tDCS on the amplitudes of the later
I waves (the sum of the amplitudes of all
waves following the I1 wave). Later I-wave
amplitudes were increased after the end of
tDCS. *P ⬍ 0.05.

level (Supplemental Figs. S1–S5). Subjects 2 and 3 were amplitudes and the low number of patients available for epi-
studied again 20 min after the end of tDCS. At this time the dural recordings. As our a priori hypothesis was to find a
descending volleys had completely recovered to pre-tDCS decrease of MEP size after cathodal tDCS—which is basically
level (Supplemental Figs. S1–S5). what we found as it is described by the time course shown in
When the analysis was repeated with the Friedman test, Fig. 3B—we performed a paired t-test only at the first time
similar results were obtained (Table 3). points, without applying correction for multiple comparisons.
Cathodal tDCS. Mean I wave and MEP amplitudes are Using this approach, we found that MEP amplitudes were
reported in Table 2. In Fig. 3 amplitude ratio is reported significantly decreased 0 – 4 min after cathodal tDCS (0 –2 min,
(post/baseline). Figure 3A shows the time course of the effect P ⫽ 0.0384; 2– 4 min, P ⫽ 0.0120). Moreover, there was a
of cathodal tDCS on the amplitudes of the total volley. Mean certain degree toward a linear correlation between total volley
total volley was decreased by ⬃30% relative to the baseline and MEP amplitude changes immediately after the tDCS ap-
value 0 – 4 min after the end of tDCS. A repeated-measures plication (Spearman test, Post 1: r2 ⫽0.731, P ⫽ 0.037; Post
ANOVA on normalized data showed a significant effect of 2: r2 ⫽0.386, P ⫽ ns).
time (F5,20 ⫽ 8.483, P ⫽ 0.0001). The consequence of these Figure 3, C and D, show the time course of the effect of
changes could be observed in MEPs we recorded from the FDI. cathodal tDCS on the amplitudes of the I1 or later I waves.
Similarly, post hoc analysis conducted for MEP amplitudes Mean I1 wave amplitude was unchanged after the end of tDCS
revealed that total volley amplitudes were significantly de- (F5,20 ⫽ 1.764, P ⫽ 0.166). However, later I wave amplitudes
creased within the first 4 min after cathodal tDCS (0 –2 min, were reduced after the end of tDCS. A repeated-measures
P ⫽ 0.0097; 2– 4 min, P ⫽ 0.0008). MEP amplitudes were ANOVA on normalized data showed a significant effect of
decreased immediately after cathodal tDCS (on average for time (F5,20 ⫽ 8.669, P ⫽ 0.0005). Post hoc analysis revealed
⬃15% of their pre-tDCS size); however, the overall change did that later I wave amplitudes were significantly reduced within
not reach significance (F5,20 ⫽ 2.204, P ⫽ 0.094) (Fig. 3B). the first 4 min after cathodal tDCS (0 –2 min, P ⫽ 0.0015; 2– 4
The lack of significant modulation of MEP amplitudes after min, P ⫽ 0.0014). Cathodal tDCS reduced mean later I-wave
cathodal tDCS (considering the whole time course of the amplitude to ⬃40% (0 – 4 min) of baseline value.
experiments) may be explained by the high variability of MEP When the analysis was repeated with the Friedman test,
similar results were obtained (Table 3).
Table 3. Friedman test
I1 Waves Later I Waves Total Volley MEP
DISCUSSION

Anodal tDCS (n ⫽ 6) The present results demonstrate that tDCS of the primary
␹2 11.543 19.621 17.228 12.702 motor cortex leads to pronounced and polarity-specific changes
P 0.021 0.001 0.002 0.013 of corticospinal activity in conscious humans. Anodal tDCS
increased whereas cathodal tDCS decreased the excitability of
Cathodal tDCS (n ⫽ 5)
cortical circuits generating the I waves in the corticospinal
␹2 8.797 19.099 16.412 10.313 system. These results support the concept that anodal tDCS
P 0.117 0.002 0.006 0.067
effects originate—at least partially—at the cortical level.
J Neurophysiol • VOL 105 • JUNE 2011 • www.jn.org
 I-WAVE MODULATION BY tDCS 2807

Fig. 3. Effects of cathodal tDCS on the am-

plitude of I waves and MEPs in individual
subjects (dashed lines). The continuous line
represents the grand mean of all subjects.
Error bars indicate SD. A: time course of the
effect of cathodal tDCS on the amplitudes of
the total volley. Mean total volley was de-
creased after the end of tDCS. B: time course
of the effects of cathodal tDCS on MEP
amplitudes. Mean MEP amplitudes were de-
creased after the end of cathodal tDCS.
C: time course of the effect of cathodal tDCS
on the amplitudes of the I1 waves. Mean
I1-wave amplitude was unchanged after the

Downloaded from http://jn.physiology.org/ by 10.220.33.5 on September 25, 2017

end of tDCS. D: time course of the effect of
cathodal tDCS on the amplitudes of later I
waves. Mean later I-wave amplitudes were
reduced after the end of tDCS. *P ⬍ 0.05;
#P ⬍ 0.05 without correction for multiple
comparisons (see RESULTS).

Anodal tDCS increased the excitability of cortical circuits Lazzaro et al. 1999a), or short-latency afferent inhibition pro-
generating I waves in the corticospinal system, including the I1 duced by stimulation of the median nerve (Tokimura et al.
wave, whereas cathodal tDCS affected later I waves. Although 2000). Therefore, it has been suggested that different neurons
both I1 and later I waves are facilitated by anodal tDCS, our are involved in the generation of the I1 wave and later I waves
data show that these effects might have a different time course. and that only those generating the latter are the target of the
In fact, we found that I1 wave is significantly increased only in inhibitory projections (Di Lazzaro et al. 2004). This may
the first 2 min after anodal tDCS application, while the effects explain the partly discernable effects of stimulation on I1 and
on later I waves are significant for 4 min. However, since I1 later I waves observed in the present study. While excitatory
was trendwise altered also at later time points, and the vari- anodal tDCS resulted in changes of both I1 and later I waves,
ability of the data was relatively large, this should be explored inhibitory cathodal tDCS mainly modulated later I waves.
in larger detail in future studies. The effect on corticospinal Anodal tDCS. In the first minutes after anodal tDCS, both I1
activity after the end of the conditioning period parallels the waves and later waves are facilitated; this can be explained by
time course of MEP changes that was described in other studies a facilitatory effect on the corticospinal neurons. The I1 wave
using similar parameters of tDCS (Lang et al. 2004; Nitsche is considered to originate from stimulation of the axons of
and Paulus 2001; Nitsche et al. 2003b). Concerning MEP cortico-cortical or thalamo-cortical connections (Di Lazzaro et
amplitudes, we found that tDCS-induced MEP changes had a al. 1998b). Enhanced excitability of the corticospinal neurons
similar time course compared with the changes of corticospinal as the main mechanism of facilitation of the I1 wave—and of
activity. The results from the present study fit well with those later waves—is, however, not probable because if this was the
obtained in tDCS studies with noninvasive recording tech- case we would expect a parallel reduction of MEP thresholds,
niques. which has not been observed (Nitsche and Paulus 2000).
I1 wave and later I waves are differentially modulated by Alternatively, anodal tDCS of the motor cortex may activate
tDCS. D and I waves refer to high-frequency (⬃600 Hz) cortico-cortical and thalamo-cortical fibers and interneurons
repetitive discharges of corticospinal fibers produced by elec- distant from the corticospinal cell soma. This would explain
trical stimulation of the motor cortex (Patton and Amassian why the motor threshold is not strongly affected by anodal
1954; Ziemann and Rothwell 2000). The D wave persists tDCS. In any case, we cannot completely exclude that anodal
during anesthesia, cooling, or after cortical ablation, whereas I tDCS produces subtle changes in excitability of corticospinal
waves require intact and excitable gray matter (Amassian et al. cells lasting a few minutes after the end of the stimulation.
1987; Patton and Amassian 1954). The exact nature of the Moreover, we cannot definitely conclude that the I1 wave
generation of I waves is still unclear, but there is convincing changes are primarily produced directly by tDCS, as it is
evidence that they originate in the motor cortex, mainly possible that these effects can be secondary to the facilitation
through activation of cortico-cortical projections onto cortico- of later I waves.
spinal neurons (Ziemann and Rothwell 2000). In contrast to Our results support the concept that the effects induced by
later I waves, the I1 wave is rarely affected by any conditioning anodal tDCS are at least partially located intracortically and
inputs, whether a subthreshold magnetic stimulus given that tDCS of the primary motor cortex modulates the activity of
through the same coil (Di Lazzaro et al. 1998a; Hanajima et al. cortical interneurons projecting onto pyramidal tract neurons.
1998; Nakamura et al. 1997), a conditioning magnetic stimulus Cathodal tDCS. The results of our study show that cathodal
applied to the motor cortex of the opposite hemisphere (Di stimulation modulates the excitability of cortical structures
J Neurophysiol • VOL 105 • JUNE 2011 • www.jn.org
2808 I-WAVE MODULATION BY tDCS

generating the later I waves. Since the later I waves are the first correlation; this is particularly relevant when tDCS is used
to disappear during cooling of the motor cortex (Amassian et because its effects clearly extend beyond the cortical represen-
al. 1987), they are thought to originate from more superficial tation of FDI. 3) Finally, it should be considered that the I
cortical layers. Moreover, later I waves are targeted by inhib- waves might not represent the total descending activity and
itory projections (Di Lazzaro et al. 2004). There is evidence some asynchronous descending activity might also be present
that excitatory and inhibitory intracortical circuits have a dif- (Di Lazzaro et al. 2006); thus the correlation between I waves
ferent threshold (Ziemann et al. 1996). Thus it can be specu- and MEP might be limited. However, taking into account the
lated that cathodal stimulation facilitates inhibitory connec- direction of MEP and I-wave modulation, it seems most
tions or that it produces disfacilitation (e.g., hyperpolarization) conclusive that at least a part of the MEP effects is explained
of excitatory connections leading to a selective suppression of by changes in amplitude of the I waves.
later I waves. Because of the small number of subjects studied, Does tDCS act directly or indirectly on the I waves? The
we cannot rule out that some questions cannot be answered effects of tDCS may be due to direct effects of currents on the
with this set of data. For example, the I1-wave amplitudes generators of the I waves at the cortical level. This direct effect
showed a trend toward suppression after cathodal tDCS. We can have different neural targets depending on polarity and
would like to remark that our data suggest that there are intensity of the currents applied. High-intensity anodal tDCS

Downloaded from http://jn.physiology.org/ by 10.220.33.5 on September 25, 2017

differential effects of cathodal tDCS on I1 wave and later I might modulate corticospinal neurons directly (Ardolino et al.
waves, but we cannot definitely exclude an effect also on the I1 2005), while less intense currents might have a preferential
wave generators. activation of axons of the cortical interneurons and/or the end
In conclusion, our results support the concept that the effects of the axons originated from other cortical or subcortical
induced by cathodal tDCS are at least partially located at the structures. Alternatively, the effects of tDCS can indirectly
cortical level. modulate the I waves. tDCS applied over the motor cortex and
Study limitations. We would like to report some study contralateral orbita activates brain areas far away from the
limitations mainly due to the impossibility of studying a larger electrode location (Lang et al. 2005). Many of the areas
population and conducting longer experimental sessions. The activated/deactivated by the tDCS have direct or indirect con-
lack of a sham tDCS condition could question the fact that the nection to the motor cortex, and may therefore be the respon-
reported effects on I waves are specifically caused by tDCS, sible for the I-wave modulation induced by tDCS.
and not by any unspecific “placebo” or “expectancy” effect. Comparison between tDCS and repetitive TMS protocols.
Unfortunately, the small number of patients with externalized Another method for inducing cortical excitability changes in
epidural electrodes available makes the sham-real design un- humans noninvasively is repetitive TMS (rTMS). Like tDCS,
reliable. However, in our opinion the opposite directions of the rTMS can produce effects on cortical excitability that outlast
effects of anodal and cathodal tDCS make any unspecific effect the period of stimulation. There are fundamental differences
very unlikely. Since patients were blinded about tDCS condi- between tDCS and rTMS, the former manipulating membrane
tions (anodal or cathodal), effects of “expectancy” are also potential and the latter inducing discharging of fibers to pro-
unlikely. In any case, we cannot completely rule out that some duce their respective long-lasting effects on cortical excitabil-
of the reported effects may have been caused by a placebo ity. Although the changes produced by rTMS and tDCS pro-
effect. tocols as evaluated with MEP recording are apparently similar,
On the basis of our data, we cannot rule out that MEP the effects may involve different structures within the central
changes may include possible effects of tDCS on spinal cord motor circuits. The cortical circuits generating the I1 and late
excitability. However, in the light of the current data on tDCS I waves can be modulated independently. The facilitatory
(with a stimulation protocol as used here) it seems unlikely that protocols like intermittent theta-burst stimulation (iTBS) and
changes of spinal cord excitability as a consequence of tDCS paired associative stimulation using a facilitatory interstimulus
predominantly contribute to the observed changes on cortico- interval (PAS⫹) selectively modulate cortico-cortical circuits
spinal volleys and MEP (Nitsche and Paulus 2001; Nitsche et generating the late I waves (Di Lazzaro et al. 2008, 2009b,
al. 2003a, 2003b, 2005), although minor contributions cannot 2010). These cortico-cortical circuits are facilitated also by
be excluded that might become more prominent with larger anodal tDCS, but tDCS seems also to facilitate the monosyn-
current density (Ardolino et al. 2005). aptic cortical circuit generating the I1 wave. A modulation of
Concerning MEP amplitudes, our a priori hypothesis was to the circuit generating the I1 wave has also been reported with
find an increase of MEP size after anodal tDCS and a decrease the use of magnetic stimulation with the continuous theta-burst
of MEP size after cathodal tDCS, and this is basically what we stimulation (cTBS) protocol (Di Lazzaro et al. 2005; Huang et
found as shown by the time course of MEP changes displayed al. 2005). In the case of cTBS a suppression instead of a
in Figs. 2B and 3B. We found that tDCS-induced MEP changes facilitation is observed, but interestingly both anodal tDCS and
had a similar time course compared with the changes of TBS stimulation (performed at subthreshold intensities) might
corticospinal activity. However, we only found a weak corre- not discharge the cortical axons; thus the induced excitability
lation between MEP and total volley changes after anodal and changes might not be related to synaptic activation during
cathodal tDCS. There are several possible explanation for this. stimulation.
1) First of all, the high variability of mean MEP amplitude in A different mechanism of inhibition of the central motor
the small group of subjects available for this kind of invasive system has been proposed for different rTMS protocols. rTMS
studies should be considered. 2) It should also be considered delivered as 1 Hz, paired associative stimulation using inhib-
that the descending volleys are destined for several different itory interstimulus intervals (PAS⫺) (Di Lazzaro et al. 2009a),
muscles and not only for the FDI from which MEPs were and cathodal tDCS selectively suppress the cortico-cortical
recorded. Thus it might not be surprising to find a low level of circuits generating the late I waves.
J Neurophysiol • VOL 105 • JUNE 2011 • www.jn.org
 I-WAVE MODULATION BY tDCS 2809

It is interesting to consider that other forms of rTMS pro- descending volleys evoked by transcranial stimulation in conscious humans.
ducing facilitation of MEPs, like repetitive paired-pulse trans- J Physiol 508: 625– 633, 1998b.
Di Lazzaro V, Oliviero A, Profice P, Saturno E, Pilato F, Insola A,
cranial magnetic stimulation at I wave periodicity, do not Mazzone P, Tonali P, Rothwell JC. Comparison of descending volleys
change I waves at all (Di Lazzaro et al. 2007). Knowledge of evoked by transcranial magnetic and electric stimulation in conscious
the physiological basis of the tDCS and rTMS protocols might humans. Electroencephalogr Clin Neurophysiol 109: 397– 401, 1998c.
be important for future clinical application of these stimulation Di Lazzaro V, Oliviero A, Pilato F, Saturno E, Dileone M, Mazzone P,
protocols. The discernable physiological effects could result in Insola A, Tonali PA, Rothwell JC. The physiological basis of transcranial
different effects in neurological and psychiatric disorders, motor cortex stimulation in conscious humans. Clin Neurophysiol 115:
255–266, 2004.
dependent on their pathophysiological substrates.
Di Lazzaro V, Pilato F, Saturno E, Oliviero A, Dileone M, Mazzone P,
To summarize, epidural recordings of corticospinal activity Insola A, Tonali PA, Ranieri F, Huang YZ, Rothwell JC. Theta-burst
indicate that anodal tDCS possibly develops its facilitatory repetitive transcranial magnetic stimulation suppresses specific excitatory
effects on MEP amplitudes by an increase of activity in cortical circuits in the human motor cortex. J Physiol 565: 945–950, 2005.
networks generating both I1 and later I waves, with a different Di Lazzaro V, Pilato F, Oliviero A, Dileone M, Saturno E, Mazzone P,
time course regarding the two components. Cathodal tDCS Insola A, Profice P, Ranieri F, Capone F, Tonali PA, Rothwell JC.
mainly inhibits those networks generating the later I waves. Origin of facilitation of motor-evoked potentials after paired magnetic

Downloaded from http://jn.physiology.org/ by 10.220.33.5 on September 25, 2017

stimulation: direct recording of epidural activity in conscious humans. J
These results confirm that tDCS-induced aftereffects are at Neurophysiol 96: 1765–1771, 2006.
least partially of cortical origin. The pattern of changes in Di Lazzaro V, Thickbroom GW, Pilato F, Profice P, Dileone M, Mazzone
corticospinal activity is distinctly different from those de- P, Insola A, Ranieri F, Tonali PA, Rothwell JC. Direct demonstration of
scribed after other noninvasive brain stimulation techniques. the effects of repetitive paired-pulse transcranial magnetic stimulation at
I-wave periodicity. Clin Neurophysiol 118: 1193–1197, 2007.
Di Lazzaro V, Pilato F, Dileone M, Profice P, Oliviero A, Mazzone P,
ACKNOWLEDGMENTS Insola A, Ranieri F, Meglio M, Tonali PA, Rothwell JC. The physiolog-
We thank Dr. Juan Aguilar for useful discussions. ical basis of the effects of intermittent theta burst stimulation of the human
motor cortex. J Physiol 586: 3871–3879, 2008.
Di Lazzaro V, Dileone M, Pilato F, Profice P, Oliviero A, Mazzone P,
GRANTS Insola A, Capone F, Ranieri F, Tonali PA. LTD-like plasticity induced by
paired associative stimulation: direct evidence in humans. Exp Brain Res
This work was supported by the “Young Investigator Award” (Stipendium 194: 661– 664, 2009a.
für junge Wissenschaftler) from the German Society for Clinical Neurophys- Di Lazzaro V, Dileone M, Pilato F, Profice P, Oliviero A, Mazzone P,
iology (DGKN) for N. Lang and by the “FISCAM,” Gobierno de Castilla La Insola A, Capone F, Ranieri F, Tonali PA. Associative motor cortex
Mancha (Spain). plasticity: direct evidence in humans. Cereb Cortex 19: 2326 –2330, 2009b.
Di Lazzaro V, Profice P, Pilato F, Dileone M, Oliviero A, Ziemann U. The
effects of motor cortex rTMS on corticospinal descending activity. Clin
DISCLOSURES Neurophysiol 121: 464 – 473, 2010.
No conflicts of interest, financial or otherwise, are declared by the author(s). Hanajima R, Ugawa Y, Terao Y, Sakai K, Furubayashi T, Machii K,
Kanazawa I. Paired-pulse magnetic stimulation of the human motor cortex:
differences among I waves. J Physiol 509: 607– 618, 1998.
REFERENCES Huang YZ, Edwards MJ, Rounis E, Bhatia KP, Rothwell JC. Theta burst
stimulation of the human motor cortex. Neuron 45: 201–206, 2005.
Amassian VE, Stewart M, Quirk GJ, Rosenthal JL. Physiological basis of Lang N, Nitsche MA, Paulus W, Rothwell JC, Lemon RN. Effects of
motor effects of a transient stimulus to cerebral cortex. Neurosurgery 20: transcranial direct current stimulation over the human motor cortex on
74 –93, 1987. corticospinal and transcallosal excitability. Exp Brain Res 156: 439 – 443,
Ardolino G, Bossi B, Barbieri S, Priori A. Non-synaptic mechanisms 2004.
underlie the after-effects of cathodal transcutaneous direct current stimula- Lang N, Siebner HR, Ward NS, Lee L, Nitsche MA, Paulus W, Rothwell
tion of the human brain. J Physiol 568: 653– 663, 2005. JC, Lemon RN, Frackowiak RS. How does transcranial DC stimulation of
Bindman LJ, Lippold OC, Redfearn JW. Long-lasting changes in the level the primary motor cortex alter regional neuronal activity in the human brain?
of the electrical activity of the cerebral cortex produced by polarizing Eur J Neurosci 22: 495–504, 2005.
currents. Nature 196: 584 –585, 1962. Liebetanz D, Nitsche MA, Tergau F, Paulus W. Pharmacological approach
Bindman LJ, Lippold OC, Redfearn JW. The action of brief polarizing to the mechanisms of transcranial DC-stimulation-induced after-effects of
currents on the cerebral cortex of the rat (1) during current flow and (2) in human motor cortex excitability. Brain 125: 2238 –2247, 2002.
the production of long-lasting after-effects. J Physiol 172: 369 –382, 1964. Nakamura H, Kitagawa H, Kawaguchi Y, Tsuji H. Intracortical facilitation
Boros K, Poreisz C, Münchau A, Paulus W, Nitsche MA. Premotor and inhibition after transcranial magnetic stimulation in conscious humans.
transcranial direct current stimulation (tDCS) affects primary motor excit- J Physiol 498: 817– 823, 1997.
ability in humans. Eur J Neurosci 27: 1292–1300, 2008. Nitsche MA, Paulus W. Excitability changes induced in the human motor
Creutzfeldt OD, Fromm GH, Kapp H. Influence of transcortical d-c currents cortex by weak transcranial direct current stimulation. J Physiol 527:
on cortical neuronal activity. Exp Neurol 5: 436 – 452, 1962. 633– 639, 2000.
Di Lazzaro V, Oliviero A, Profice P, Insola A, Mazzone P, Tonali P, Nitsche MA, Paulus W. Sustained excitability elevations induced by trans-
Rothwell JC. Direct demonstration of interhemispheric inhibition of the cranial DC motor cortex stimulation in humans. Neurology 57: 1899 –1901,
human motor cortex produced by transcranial magnetic stimulation. Exp 2001.
Brain Res 124: 520 –524, 1999a. Nitsche MA, Nitsche MS, Klein CC, Tergau F, Rothwell JC, Paulus W.
Di Lazzaro V, Oliviero A, Profice P, Insola A, Mazzone P, Tonali P, Level of action of cathodal DC polarisation induced inhibition of the human
Rothwell JC. Effects of voluntary contraction on descending volleys motor cortex. Clin Neurophysiol 114: 600 – 604, 2003a.
evoked by transcranial electrical stimulation over the motor cortex hand area Nitsche MA, Fricke K, Henschke U, Schlitterlau A, Liebetanz D, Lang N,
in conscious humans. Exp Brain Res 124: 525–528, 1999b. Henning S, Tergau F, Paulus W. Pharmacological modulation of cortical
Di Lazzaro V, Restuccia D, Oliviero A, Profice P, Ferrara L, Insola A, excitability shifts induced by transcranial direct current stimulation in
Mazzone P, Tonali P, Rothwell JC. Magnetic transcranial stimulation at humans. J Physiol 553: 293–301, 2003b.
intensities below active motor threshold activates intracortical inhibitory Nitsche MA, Cohen LG, Wassermann EM, Priori A, Lang N, Antal A,
circuits. Exp Brain Res 119: 265–268, 1998a. Paulus W, Hummel F, Boggio PS, Fregni F, Pascual-Leone A. Trans-
Di Lazzaro V, Restuccia D, Oliviero A, Profice P, Ferrara L, Insola A, cranial direct current stimulation: state of the art 2008. Brain Stimul 1:
Mazzone P, Tonali P, Rothwell JC. Effects of voluntary contraction on 206 –223, 2008.

J Neurophysiol • VOL 105 • JUNE 2011 • www.jn.org

2810 I-WAVE MODULATION BY tDCS

Nitsche MA, Seeber A, Frommann K, Klein CC, Rochford C, Nitsche MS, Rothwell JC, Hallett M, Berardelli A, Eisen A, Rossini P, Paulus W.
Fricke K, Liebetanz D, Lang N, Antal A, Paulus W, Tergau F. Modu- Magnetic stimulation: motor evoked potentials. The International Federation
lating parameters of excitability during and after transcranial direct current of Clinical Neurophysiology. Electroencephalogr Clin Neurophysiol Suppl
stimulation of the human motor cortex. J Physiol 568: 291–303, 2005. 52: 97–103, 1999.
Patton HD, Amassian VE. Single and multiple-unit analysis of cortical stage Tokimura H, Di Lazzaro V, Tokimura Y, Oliviero A, Profice P, Insola A,
of pyramidal tract activation. J Neurophysiol 17: 345–363, 1954. Mazzone P, Tonali P, Rothwell JC. Short latency inhibition of human hand
Paulus W, Classen J, Cohen LG, Large CH, Di Lazzaro V, Nitsche MA, motor cortex by somatosensory input from the hand. J Physiol 523: 503–
Pascual-Leone A, Rosenow F, Rothwell JC, Ziemann U. State of the art: 513, 2000.
pharmacologic effects on cortical excitability measures tested by transcra- Ziemann U, Rothwell JC. I-waves in motor cortex. J Clin Neurophysiol 17:
nial magnetic stimulation. Brain Stimul 1: 151–163, 2008. 397– 405, 2000.
Purpura DP, McMurtry JG. Intracellular activities and evoked potential Ziemann U, Rothwell JC, Ridding MC. Interaction between intracortical
changes during polarization of motor cortex. J Neurophysiol 28: 166 –185, inhibition and facilitation in human motor cortex. J Physiol 496: 873– 881,
1965. 1996.

Downloaded from http://jn.physiology.org/ by 10.220.33.5 on September 25, 2017

J Neurophysiol • VOL 105 • JUNE 2011 • www.jn.org