Time course of the induction of homeostatic plasticity generated by repeated transcranial direct current stimulation (tDCS) of the human motor cortex

Article (PDF Available)inJournal of Neurophysiology 105(3):1141-9 · December 2010with26 Reads
DOI: 10.1152/jn.00608.2009 · Source: PubMed
Abstract
Several mechanisms have been proposed that control the amount of plasticity in neuronal circuits and guarantee dynamic stability of neuronal networks. Homeostatic plasticity suggests that the ease with which a synaptic connection is facilitated/suppressed depends on the previous amount of network activity. We describe how such homeostatic-like interactions depend on the time interval between two conditioning protocols and on the duration of the preconditioning protocol. We used transcranial direct current stimulation (tDCS) to produce short-lasting plasticity in the motor cortex of healthy humans. In the main experiment, we compared the aftereffect of a single 5-min session of anodal or cathodal tDCS with the effect of a 5-min tDCS session preceded by an identical 5-min conditioning session administered 30, 3, or 0 min beforehand. Five-minute anodal tDCS increases excitability for about 5 min. The same duration of cathodal tDCS reduces excitability. Increasing the duration of tDCS to 10 min prolongs the duration of the effects. If two 5-min periods of tDCS are applied with a 30-min break between them, the effect of the second period of tDCS is identical to that of 5-min stimulation alone. If the break is only 3 min, then the second session has the opposite effect to 5-min tDCS given alone. Control experiments show that these shifts in the direction of plasticity evolve during the 10 min after the first tDCS session and depend on the duration of the first tDCS but not on intracortical inhibition and facilitation. The results are compatible with a time-dependent "homeostatic-like" rule governing the response of the human motor cortex to plasticity probing protocols.
Time course of the induction of homeostatic plasticity generated by repeated
transcranial direct current stimulation of the human motor cortex
K. Fricke,
1,2
* A. A. Seeber,
1,2
* N. Thirugnanasambandam,
2
* W. Paulus,
2
M. A. Nitsche,
2
*
and J. C. Rothwell
1
*
1
Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, University College of London,
London, United Kingdom; and
2
Department of Clinical Neurophysiology, Georg-August-University, Göttingen, Germany
Submitted 14 July 2009; accepted in final form 17 December 2010
Fricke K, Seeber AA, Thirugnanasambandam N, Paulus W,
Nitsche MA, Rothwell JC. Time course of the induction of homeostatic
plasticity generated by repeated transcranial direct current stimulation of
the human motor cortex. J Neurophysiol 105: 1141–1149, 2011. First
published December 22, 2010; doi:10.1152/jn.00608.2009.—Several
mechanisms have been proposed that control the amount of plasticity in
neuronal circuits and guarantee dynamic stability of neuronal networks.
Homeostatic plasticity suggests that the ease with which a synaptic
connection is facilitated/suppressed depends on the previous amount of
network activity. We describe how such homeostatic-like interactions
depend on the time interval between two conditioning protocols and
on the duration of the preconditioning protocol. We used transcranial
direct current stimulation (tDCS) to produce short-lasting plasticity in
the motor cortex of healthy humans. In the main experiment, we
compared the aftereffect of a single 5-min session of anodal or
cathodal tDCS with the effect of a 5-min tDCS session preceded by an
identical 5-min conditioning session administered 30, 3, or 0 min
beforehand. Five-minute anodal tDCS increases excitability for about
5 min. The same duration of cathodal tDCS reduces excitability.
Increasing the duration of tDCS to 10 min prolongs the duration of the
effects. If two 5-min periods of tDCS are applied with a 30-min break
between them, the effect of the second period of tDCS is identical to
that of 5-min stimulation alone. If the break is only 3 min, then the
second session has the opposite effect to 5-min tDCS given alone.
Control experiments show that these shifts in the direction of plastic-
ity evolve during the 10 min after the first tDCS session and depend
on the duration of the first tDCS but not on intracortical inhibition and
facilitation. The results are compatible with a time-dependent “ho-
meostatic-like” rule governing the response of the human motor
cortex to plasticity probing protocols.
transcranial magnetic stimulation
SYNAPTIC PLASTICITY, which leads to long-term changes in cor-
tical excitability through structural or functional alterations of
neuronal connectivity, provides the neurophysiological basis
for most models of learning and memory (Hebb 1949; Abbott
and Nelson 2000). However, the positive feedback nature of
these neurophysiological alterations carries the risk of trigger-
ing an uncontrolled increase in synaptic effectiveness, which
can be potentially destabilizing and overpower all other inputs
in the system. This can be prevented by making the amount and
direction of plasticity depend on the history of activation of the
postsynaptic neuron and is formalized in the model of “homeo-
static” plasticity originally described by Bienenstock et al.
(1982) (Turrigiano and Nelson 2004). In recent years, several
animal studies have empirically confirmed this homeostatic
hypothesis (Huang et al. 1992; Wang and Wagner 1999;
Abraham et al. 2001).
Homeostatic rules of plasticity have also been explored in
humans. Iyer et al. (2003) were the first to demonstrate the
existence of homeostatic plasticity mechanisms in humans. A
brief pretreatment with repetitive transcranial magnetic stimu-
lation (rTMS) of 5– 6 Hz, which is known to increase cortical
excitability, enhanced the inhibitory effect of subsequent 1-Hz
stimulation. Siebner et al. (2004) and Lang et al. (2004)
extended these findings by exploring bidirectional homeostatic
effects in a transcranial direct current stimulation (tDCS)-
rTMS protocol on the human motor cortex, whereas Müller et
al. (2007) showed that they also applied to focal, associative
plasticity [induced by paired associative stimulation (PAS)] in
the human motor cortex. In contrast, homeostatic rules do not
necessarily apply when different plasticity-inducing protocols
are combined, such as tDCS and PAS. In this case, only
simultaneous, not successive, application of the two protocols
leads to homeostatic-like effects (Nitsche et al. 2007a). An-
other recently published study found that the efficacy of inhib-
itory cathodal tDCS was enhanced if a second period of
stimulation was given during the aftereffects of the first one,
but was reduced if the second stimulation was applied when the
aftereffects of the first DC stimulation had vanished (Monte-
Silva et al. 2010). Thus, taken together, the results of experi-
ments on homeostatic plasticity in humans are heterogeneous
and somewhat puzzling. Possible explanations for this nonuni-
formity of results might be differences in the mechanisms or
the neurons affected by each experimental protocol, the timing
of the protocols, and the duration of the induced shifts in
excitability.
In this study we aimed to explore systematically how ho-
meostatic plasticity depends on 1) the time interval between the
application of two plasticity-inducing protocols and 2) the
duration of plasticity induced by the first, preconditioning,
protocol. In the first experiment, we used 5-min periods of
tDCS, which produce aftereffects on the motor cortex lasting
for 5-10 min. In that experiment, two 5-min periods of anodal
(experiment 1a) or cathodal tDCS (experiment 1b) were sepa-
rated by an interval of 30 min (i.e., when the aftereffects of the
first protocol had disappeared: 5-30-5 min), 3 min (when the
aftereffects of the first protocol were still present: 5-3-5 min),
or 0 min (5-0-5 min, corresponding to 10 min of continuous
tDCS). The effects of the second period of tDCS were com-
pared with those of a single session of 5-min tDCS. In a control
* K. Fricke, A. A. Seeber, N. Thirugnanasambandam, M. A. Nitsche, and
J. C. Rothwell contributed equally to this work.
Address for reprint requests and other correspondence: M. A. Nitsche, Dept.
of Clinical Neurophysiology, Georg-August-Univ., Robert Koch Strasse 40,
D-37075 Göttingen, Germany (e-mail: mnitsch1@gwdg.de).
J Neurophysiol 105: 1141–1149, 2011.
First published December 22, 2010; doi:10.1152/jn.00608.2009.
11410022-3077/11 Copyright © 2011 the American Physiological Societywww.jn.org
experiment (experiment 2), we aimed to explore the time
course of interaction in more detail by applying a second
period of anodal tDCS 1, 10, and 20 min after the first one. In
a further control experiment (experiment 3), we explored the
dependency of the aftereffects of repeated anodal tDCS on the
duration of the first tDCS session by combining a second
conditioning protocol of 5-min tDCS with a preconditioning
stimulation of 7 min in duration. Finally, we explored whether
homeostatic effects depend on changes of intracortical inhibi-
tion and facilitation to learn more about the physiological
foundation of this phenomenon (experiment 4).
METHODS
Subjects
Six male and two female healthy subjects treated with anodal tDCS
(mean age, 33.5 yr; age range, 23– 49 yr) and six males and three
females treated with cathodal tDCS (mean age, 32 yr; age range,
24 –37 yr) participated in experiment 1. Four males and four females
(mean age, 24.3 yr; age range, 21–29 yr) were included in experiment
2. Five males and seven females (mean age, 26.4 yr; age range, 22–30
yr) were included in experiment 3. Three males and five females
(mean age, 31.0 yr; age range, 24 –37 yr) took part in the paired-pulse
experiment (experiment 4). Within experiments 1a (anodal tDCS), 1b
(cathodal tDCS), 2, 3, and 4, a complete crossover design was applied.
Subjects differed between the single experiments. Subjects recruited
for experiment 4 were a subgroup of subjects who participated in
experiment 1a (anodal stimulation). To avoid interference effects, a
break of at least 1 wk was obligatory between experimental sessions.
All participants were free of acute or chronic neurological, psychiat-
ric, or medical diseases and did not take any medication. The proce-
dures were approved by the Joint Ethics Committee of the National
Hospital for Neurology and Neurosurgery, the Institute of Neurology
(University College London), and the Ethics Committee of the Uni-
versity of Göttingen and were performed according to the ethical
standards laid down in the Declaration of Helsinki.
Direct Current Stimulation of the Motor Cortex
Continuous direct currents were transferred by a saline-soaked pair
of surface sponge electrodes (35 cm
2
) and delivered by a specially
developed, battery-driven constant-current stimulator (Schneider
Electronic, Gleichen, Germany) with a maximum output of 2 mA. The
motor cortical electrode was fixed over the representational field of
the right first dorsal interosseus muscle (FDI) as identified by TMS.
The other electrode was placed contralaterally above the right orbit,
since this arrangement is known to result in significant excitability
changes of the primary motor cortex (Nitsche and Paulus 2000). The
terms “anodal” or “cathodal” stimulation always refer to the polarity
of the motor cortex tDCS electrode. Anodal and cathodal stimulation
were applied with a current intensity of 1 mA (current density, 0.03
mA/cm
2
), since this intensity has been shown to be painless but is
strong enough to induce stable effects on motor cortex excitability
(Nitsche and Paulus 2000).
Monitoring of Motor Cortex Excitability
Because TMS has been shown to be a reliable tool for the
investigation of corticospinal excitability (Rothwell 1993), motor-
evoked potentials (MEPs) of the right FDI were obtained by stimu-
lation of its motor-cortical representational field by single-pulse TMS.
Stimulation was induced by a Magstim 200 magnetic stimulator
(Whiteland, Dyfed, UK) and a figure-of-eight magnetic coil (diameter
of one winding, 70 mm; peak magnetic field, 2.2 T). The coil was held
tangentially to the skull, with the handle pointing backward and
laterally at 45° from midline. The optimal coil position was defined as
the site where stimulation resulted consistently in the largest MEP.
Surface electromyogram (EMG) was recorded from the right FDI
using Ag-AgCl electrodes in a belly-tendon montage. Raw signals
were amplified, band-pass filtered (3 Hz to 1 kHz), and digitized at a
sample rate of 5 kHz using a CED 1401 laboratory interface (Cam-
bridge Electronic Design, Cambridge, UK) controlled by Signal
software (CED version 2.13). They were further relayed into a
laboratory computer for off-line analysis.
In experiments 1–3, single-pulse TMS was used to test the influ-
ence of the tDCS protocol on global corticospinal excitability (Roth-
well 1993). To test the specific influence of the protocol on intracor-
tical inhibition and facilitation, we chose the paired-pulse paradigm
introduced by Kujirai et al. (1993) for experiment 4.
Experimental Procedures
Each experiment was conducted in a repeated-measures design
with the order of experimental sessions randomized between subjects.
The volunteers were seated in a comfortable chair with a high back
against which they could lean their heads. The left motor-cortical
representational field of the right FDI was identified using TMS (the
coil position that led to the largest MEPs of FDI). For all experiments,
the intensity of the stimulator output was adjusted for baseline
recordings so that the average stimulus led to an MEP of 1mVin
30 baseline sweeps. The motor cortical tDCS electrode was fixed on
the FDI hot spot by means of a broad rubber band put around the head.
The other electrode on the contralateral forehead, just above the orbit,
was attached respectively. Both electrodes were covered by a thin wet
sponge to improve conductance and to minimize uncomfortable (e.g.,
itching) sensations during stimulation. The current was ramped at the
beginning and the end of the stimulation for 4 s. Nevertheless, some
subjects felt a slight scalp itching sensation under the electrode
contact points during current flow. The course of experiments 1–3 is
depicted in Fig. 1. Throughout the experiments, as well as the
intervals between DC stimulation, participants were resting and told to
stay relaxed, awake, keep attention at the same level, and not think
about things of major personal importance.
Experiment 1. The experiment consisted of four sessions with
anodal (experiment 1a) or cathodal tDCS (experiment 1b), respec-
tively, per subject group. First, baseline corticospinal excitability was
measured by recording 30 TMS stimuli at 0.25 Hz with a stimulator
output intensity that on average elicited MEP amplitudes of 1 mV.
Afterward, tDCS was performed as follows: 1) 5-min single stimula-
tion (5-0-0 min); 2) 5-min repeated stimulation, 30-min inter-tDCS
break (5-30-5 min); 3) 5-min repeated stimulation, 3-min inter-tDCS
break (5-3-5 min); and 4) 5-min repeated stimulation, 0-min inter-
tDCS break (5-0-5 min).
It is known that 5 min of tDCS (condition 1 above) results in
polarity-specific aftereffects lasting until approximately minute 5 after
the end of stimulation (Nitsche and Paulus 2000). In condition 2, the
second tDCS was performed well beyond the point where the after-
effects of the first tDCS session were expected to have vanished. In
condition 3, an interval of 3 min between tDCS sessions was chosen.
Thus, in this condition, we chose an inter-tDCS interval in which the
aftereffects of the first tDCS are known to still be present when the
second stimulation is performed. In condition 4, there was no break
between the two 5-min sessions.
After DC stimulation was finished, MEPs at 0.25-Hz frequency
were recorded continuously until minute 5 after tDCS, with baseline
TMS intensity. From minute 10 up to minute 30, further 30 MEPs
were measured at 0.25 Hz every 5th minute. Furthermore, 30 MEPs
were recorded at minutes 60 and 90 after the end of tDCS.
Experiment 2. In this experiment, we aimed to explore the time
course of homeostatic effects elicited by anodal tDCS to a larger
extent. The course of the experiment was identical to that of
experiment 1a with the exception that the tDCS repetition intervals
1142 HOMEOSTATIC PLASTICITY BY REPEATED tDCS
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VOL 105 MARCH 2011 www.jn.org
differed. tDCS was performed as follows: 1) 5-min single stimu-
lation (5-0-0 min); 2) 5-min repeated stimulation, 20-min inter-
tDCS break (5-20-5 min); 3) 5-min repeated stimulation, 10-min
inter-tDCS break (5-10-5 min); and 4) 5-min repeated stimulation,
1-min inter-tDCS break (5-1-5 min).
Experiment 3. In this experiment, we aimed to explore whether the
time course and duration of the aftereffects induced by repeated
anodal tDCS depend on the duration of the first tDCS application, at
least over the range of short-lasting aftereffects produced by short
periods of tDCS. The design of the experiment was identical to that of
experiment 1a with the exception that the duration of the first tDCS
application was 7 min, which induces aftereffects lasting for some
minutes longer than that of a 5-min DC stimulation but shorter than
the 30 min or more seen after 10-min stimulation (Nitsche and
Paulus 2001). tDCS was performed as follows: 1) 7-min single
stimulation (7-0-0 min); 2) repeated stimulation, 30-min inter-tDCS
break (7-30-5 min); 3) repeated stimulation, 20-min inter-tDCS break
(7-20-5 min); 4) repeated stimulation, 10-min inter-tDCS break (7-
10-5 min); 5) repeated stimulation, 3-min inter-tDCS break (7-3-5
min); and 6) repeated stimulation, 1-min inter-tDCS break (7-1-5
min). Figure 1 shows a synopsis of experiments 1–3.
Experiment 4. For experiment 4, we applied the paired-pulse
stimulation technique described by Kujirai et al. (1993) to explore
homeostatic plasticity-related changes of intracortical inhibition and
facilitation. Single test pulse TMS intensity was adjusted to achieve
MEPs of 1 mV peak-to-peak amplitude. The conditioning pulse
intensity was 70% of active motor threshold (AMT). AMT was
defined as the minimum TMS intensity eliciting a MEP of a superior
size compared with spontaneous moderate muscular activity (15%
of maximum strength) in at least three of six trials and was obtained
about 10 min before tDCS. This relatively weak intensity was chosen
to prevent ceiling or floor effects of the double stimulation protocol
and is sufficient to monitor tDCS-driven changes of intracortical
facilitation and inhibition (Nitsche et al. 2005). The paired-pulse
stimulation protocol included interstimulus intervals (ISI) of 2, 3, 7,
10, and 15 ms, with the first two ISIs representing inhibitory and the
last two ISIs facilitatory intervals. The pairs of stimuli were organized
in blocks in which each paired stimulation interval and an additional
Fig. 1. Experimental approach. In experiment 1, anodal (experiment 1a) or cathodal (experiment 1b) transcranial direct current stimulation (tDCS) was applied
to the left primary motor cortical hand area (M1) on separate days. Motor-evoked potentials (MEP) of the right first dorsal interosseus muscle were recorded
following stimulation of its motor cortical representational field by single-pulse (Sp) transcranial magnetic stimulation (TMS). First, baseline corticospinal
excitability was obtained by recording 30 TMS stimuli at 0.25 Hz with a stimulator output intensity that on average elicits MEP amplitudes of 1 mV. Afterward,
anodal or cathodal tDCS (1 mA) was performed for 5 min once (5-0-0 min) or twice with an inter-tDCS break of 30 min (5-30-5 min), 3 min (5-3-5 min), or
0 min (5-0-5 min). In experiment 2, only anodal tDCS (1 mA) was performed for 5 min once (5-0-0 min) or repeated for 5 min with an inter-tDCS break of
20 min (5-20-5 min), 10 min (5-10-5 min), or 1 min (5-1-5 min). In experiment 3, preconditioning anodal tDCS was prolonged from 5 to 7 min, and the break
between the two DC stimulations was identical to those of experiments 1 and 2. For all experiments, MEPs at 0.25 Hz were recorded for the first 5 min after
tDCS. From minute 10 to minute 30, 30 MEPs were recorded every 5th minute. Furthermore, at minutes 60 and 90 after tDCS, 30 MEPs were recorded.
1143HOMEOSTATIC PLASTICITY BY REPEATED tDCS
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single test pulse were presented once. The blocks were repeated 12
times for each time bin of measurement (see below), and the order of
the different pulses was pseudorandomized between blocks.
Because of the findings in experiments 1a and 1b, anodal tDCS was
performed only for the two following protocols: 1) 5-min single stimu-
lation (5-0-0 min); and 2) 5-min repeated stimulation, 3-min inter-tDCS
pause (5-3-5 min). Twelve paired pulse blocks were obtained before as
well as directly after and 20 min after tDCS. Because we aimed to test
intracortical excitability directly after tDCS application, time restrictions
meant we were not able to adjust test pulse intensity and AMT to
post-tDCS conditions. However, according to the results of Nitsche et al.
(2005), no significant change of AMT was expected.
Calculations and Statistics
Experiment 1. MEP amplitude means were calculated for each time
bin covering baseline (Supplemental Table S1, available in the data
supplement online at the Journal of Neurophysiology web site) and
poststimulation time points. The post-tDCS MEPs were normalized
intraindividually and are given as ratios of the pre-current baselines.
A three-way repeated-measures ANOVA for all data with tDCS
polarity as a between-subject factor (due to different subject groups in
experiments 1a and 1b) and tDCS-protocol (5-0-0, 5-30-5, 5-3-5, and
5-0-5 min) and time course (1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 60, and
90 min after tDCS) as within-subject factors was calculated. A P value
0.05 was considered significant. Additional Student’s t-tests (paired
samples, 2-tailed, level of significance 0.05) were performed to test
whether the baseline MEP amplitudes differed significantly between
tDCS conditions, whether the MEP amplitudes after tDCS differed
significantly from the pre-tDCS amplitudes, and whether those dif-
ferences depended on the tDCS ISI for anodal and cathodal
stimulation.
Experiment 2. MEP amplitude means were calculated for each time
bin covering baseline and poststimulation time points. The post-tDCS
MEPs were normalized intraindividually and are given as ratios of the
pre-current baselines. A two-way repeated-measures ANOVA with
tDCS protocol (5-0-0, 5-20-5, 5-10-5, and 5-1-5 min) and time course
as within-subject factors was calculated. A P value 0.05 was
considered significant. Additional Student’s t-tests (paired samples,
2-tailed, level of significance 0.05) were performed to test whether
the baseline MEP amplitudes differed significantly between tDCS
conditions, whether the MEP amplitudes after tDCS differed signifi-
cantly from the pre-current amplitudes, and whether those differences
depended on the tDCS intervals.
Experiment 3. The calculations performed for experiment 3 were
identical to those for experiment 2 with the exception that the factor
tDCS protocol differed (7-0-0, 7-1-5, 7-3-5, 7-10-5, 7-20-5, and
7-30-5 min). For experiments 1–3, we conducted additional analyses
with nonstandardized MEP amplitude values, which are shown in the
Supplemental Material (Table S2 and Figs. S1–S3).
Experiment 4. Means of the MEP amplitudes were calculated for each
ISI and normalized to single test pulse amplitude for each time bin
intraindividually. A three-way repeated-measures ANOVA including ISI,
time point, and tDCS protocol as within-subject factors and MEP ampli-
tude as a dependent variable was calculated. A P value 0.05 was
considered significant. Student’s t-tests (paired samples, 2-tailed, level of
significance 0.05) were performed to test whether the paired pulse-
elicited MEP amplitudes differed significantly from baseline. In addition,
within each protocol we tested whether the results of the stimulation
protocols after tDCS differed from the pre-tDCS protocol.
RESULTS
Experiments 1a and 1b
The results of the ANOVA showed a significant three-way
interaction of tDCS polarity tDCS protocol time course
(Table 1). This was caused by tDCS polarity-specific effects,
which differ for the inter-tDCS intervals, as shown in Fig. 2A
for anodal and Fig. 2B for cathodal tDCS.
As expected from previous studies (Nitsche and Paulus
2000, 2001), 5-min (5-0-0 min) anodal stimulation facilitated
MEPs for the next 5 min, whereas 10-min continuous stimu-
lation (5-0-5 min) facilitated MEPs for 30 min. Aftereffects of
the 5-30-5-min protocol were identical to those of the 5-0-0-
min protocol for all time points. After 5-3-5-min conditioning,
MEPs were facilitated for 3 min and then became significantly
depressed from 10 to 30 min after tDCS. The difference
between the 5-0-0-min and the 5-3-5-min protocols was sig-
nificant at all time points from minute 5 to minute 30. Com-
pared with the 10-min continuous stimulation (5-0-5 min), the
MEP amplitude reduction was significant from minute 10 to
minute 30 after tDCS.
Cathodal 5-0-0-min tDCS significantly suppressed MEPs for
up to 5 min after tDCS, whereas in the 5-0-5-min protocol,
MEPs were significantly suppressed for 30 min. Aftereffects of
the 5-30-5-min protocol were identical to those of the 5-0-0-
min tDCS. In contrast, 5-3-5-min conditioning did not suppress
MEPs but resulted in significant facilitation of MEPs from 15
to 30 min after tDCS. The effect was significantly different
from 5-0-0-min conditioning at all time points until minute 25.
Compared with the 10-min continuous stimulation (i.e., the
5-0-5-min protocol), the difference was significant at all time
points after tDCS up to minute 60. Baseline MEP amplitudes of
Table 1. Results of ANOVAs
df F Value P Value
Experiment 1
Protocol 3 0.797 0.502
Time course 12 6.645 0.001*
Polarity 1 58.600 0.001*
Protocol x polarity 3 11.579 0.001*
Time course polarity 12 22.333 0.001*
Protocol time course 36 1.065 0.373
Protocol time course polarity 36 3.689 0.001*
Experiment 2
Protocol 3 3.001 0.054
Time course 3 2.052 0.029*
Protocol time course 9 0.846 0.721
Experiment 3
Protocol 5 2.559 0.038*
Time course 12 0.595 0.843
Protocol time course 60 1.489 0.012*
Experiment 4
Protocol 1 5.606 0.050
Time course 2 34.391 0.001*
ISI 4 15.157 0.001*
Protocol time course 2 0.929 0.418
Protocol ISI 4 0.363 0.833
Time course ISI 8 0.183 0.992
Protocol time course ISI 8 0.255 0.978
Data are results of the analyses of variance (ANOVAs). In experiment 1,
where anodal or cathodal transcranial direct current stimulation (tDCS) was
applied for 5 min and repeated after 0 min without a break or after a 3- or
30-min break. In experiment 2, the second session of anodal tDCS followed the
first after a 1-, 10-, or 20-min break. Experiment 3 included a slight prolon-
gation of the preconditioning tDCS protocol (7-min stimulation instead of 5
min). In experiment 4, intracortical inhibition and facilitation were obtained
before, immediately after, and 20 min after a single session of 5-min tDCS or
two sessions of tDCS separated by a 3-min break. df, degrees of freedom; ISI,
interstimulus interval.
1144 HOMEOSTATIC PLASTICITY BY REPEATED tDCS
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all tDCS paradigms and polarities were identical (Student’s
t-test, P 0.05).
Experiment 2
The ANOVA resulted in a significant main effect for time
course. The impact of the different anodal tDCS protocols on
MEP amplitudes is depicted in Fig. 3. Similar to experiment
1a, 5-min (5-0-0 min) anodal stimulation facilitated MEPs
during the first minutes after tDCS. However, the magnitude of
the change was smaller, perhaps due to the fact that different
individuals were tested. Aftereffects of the 5-20-5-min and the
5-1-5-min protocols did not differ significantly from baseline at
any time point. Furthermore, they did not differ significantly
from those obtained with the 5-0-0-min protocol. After 5-10-
5-min conditioning, MEPs were not facilitated at all but be-
came significantly depressed compared with baseline values
for up to 90 min after stimulation. Compared with the 5-3-5-
min protocol of experiment 1a, this effect evolved without
delay and had a longer duration.
Experiment 3
The ANOVA showed a significant main effect of tDCS
protocol and a significant interaction of tDCS protocol time
course (Table 1). Seven-minute anodal tDCS given alone
increased corticospinal excitability for up to 20 min after
stimulation. As in experiments 1 and 2, a 10-min break be-
tween consecutive tDCS protocols (7-10-5 min) reduced ex-
citability significantly within the first 5 min after tDCS, with a
smaller effect persisting to 30 min. In contrast to experiments
1 and 2, a 3-min break between tDCS protocols (7-3-5 min)
also reduced excitability within the first 5 min after tDCS, and
this persisted for up to 60 min. For the other conditions (7-1-5,
7-20-5, and 7-30-5 min), there was a tendency for the initial
increase in excitability induced by tDCS to be reduced or
abolished, but this recovered by 10-30 min after tDCS (Fig. 4).
Note that due to the design of this experiment, the effects of the
5-min tDCS were compared statistically (in Table 1) with
7-min tDCS given alone, rather than with a single period of
5-min tDCS. The limitations of this are addressed in the
DISCUSSION.
Experiment 4
The three-way repeated-measures ANOVA showed signifi-
cant main effects of the factors time course and ISI (Table 1).
Fig. 3. Time course of motor cortex excitability after 5-0-0, 5-20-5, 5-10-5, and
5-1-5 min of anodal tDCS: experiment 2. A single session of 5 min of anodal
tDCS (5-0-0 min) resulted in a significant enhancement of MEP amplitudes,
lasting for some minutes after stimulation. Two successive 5-min tDCS
stimulation sessions with a break of 1 or 20 min (5-1-5 or 5-20-5 min) resulted
in a suppression of these aftereffects. However, if the second tDCS was
administered 10 min after the first (5-10-5 min), the conditioning tDCS led to
a prolonged suppression of MEP amplitudes for up to 90 min after tDCS. MEP
amplitudes are normalized to baseline values. Values are means SE. Filled
symbols represent significant deviations from baseline with regard to each
tDCS protocol. P 0.05, significant difference relative to 5-0-0-min tDCS
protocol.
Fig. 2. Time course of motor cortex excitability after 5-0-0, 5-30-5, 5-3-5, and
5-0-5 min of anodal or cathodal tDCS: experiment 1. A: a single session of 5
min of anodal tDCS (5-0-0 min) resulted in a significant enhancement of MEP
amplitudes, lasting until about minute 5 after stimulation. Two successive
5-min tDCS sessions without a pause (5-0-5 min) resulted in a prolongation of
these aftereffects. With a rest period of 30 min between the repetitive
stimulation sessions (5-30-5 min), the effects were identical to the 5-0-0-min
protocol. However, if the second tDCS was administered 3 min after the first
5-3-5-min protocol, and thus during the aftereffects of the prior stimulation, the
conditioning tDCS led to a short-lasting facilitation, followed by a prolonged
suppression of MEP amplitudes. B: a single session of 5 min of cathodal tDCS
(5-0-0 min) resulted in significant reduction of MEP amplitudes, lasting until
about 5 min after stimulation. Two successive 5-min tDCS sessions without a
break (5-0-5 min) resulted in a prolongation of these aftereffects. With a break
of 30 min between the stimulation sessions, the effects were identical to the
single 5-0-0-min tDCS condition. However, if the second tDCS was admin-
istered 3 min after the first, and thus during the aftereffects of the prior
stimulation, it caused a nonsignificant facilitation until 5 min after tDCS,
followed by a significant facilitation of 30 min in duration. MEP amplitudes
are normalized to baseline values. Values are means SE. Filled symbols
represent significant deviations from baseline with regard to each tDCS protocol.
P 0.05, significant difference relative to 5-0-0-min tDCS protocol. P
0.05, significant difference relative to 5-0-5-min tDCS protocol.
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There was no significant main effect or interaction involving
tDCS protocols, indicating that the 5-0-0-min and the 5-3-5-
min protocols had identical effects on paired-pulse interactions
despite their different effects on single-pulse MEP amplitudes.
In both protocols, ISIs of 2 and 3 ms reduced MEP ampli-
tude relative to the single test pulse, whereas ISIs of 10 and 15
ms led to slight facilitation before tDCS. Immediately after
both tDCS protocols, the amount of inhibition was significantly
reduced and facilitation was enhanced relative to the pre-tDCS
condition. For all ISIs, MEP amplitudes returned to baseline 20
min after tDCS with regard to both tDCS protocols. Taken
together, the data indicate no significant difference at any ISI between
the 5-0-0-min and the 5-3-5-min protocols (Fig. 5, A and B).
DISCUSSION
The main result of our study is that the effects of repeated
short periods of motor cortex tDCS follow a time-dependent
rule compatible with homeostatic mechanisms. As in previous
experiments, a single tDCS session of 5-min duration increased
excitability when anodal tDCS was applied and decreased it
when cathodal tDCS was administered. If a second tDCS
session followed the first one during a critical time interval of
3 or 10 min, but not 1, 20, or 30 min, the aftereffects of tDCS
were reduced or even reversed. The results of the experiments
are compatible with the suggestion that the duration of the first
preconditioning DC stimulation has an effect on the time
course of these changes. The homeostatic effect of a 3-min
break after 5-min tDCS took 5 min to appear, whereas it
occurred almost immediately after 7 min of tDCS. Alterna-
tively, it cannot be ruled out that these differences are caused
by the different duration of the delay between the start of the
preconditioning and the end of the conditioning tDCS, which is
longer in the 7-3-5-min condition, compared with the 5-3-5-
min condition, due to the longer duration of the precondition-
ing stimulation. In this case, it might be speculated that the
system needs some minutes to develop the respective homeo-
static alterations. Interestingly, the homeostatic interactions
seem not to be related to changes of intracortical inhibition or
facilitation, as measured in the present study.
The time-dependent reversal of after effects is compatible
with a homeostatic-like mechanism that regulates the ease and
direction with which neuroplasticity can be induced according
to the previous history of activity. Similar effects have been
demonstrated in human motor cortex for different combina-
tions of plasticity-inducing protocols (Iyer et al. 2003; Lang et
al. 2004; Müller et al. 2007; Nitsche et al. 2007a; Siebner et al.
2004), such as repetitive TMS, paired associative stimulation,
Fig. 5. Time course of intracortical inhibition and facilitation for the 5-0-0-min
and 5-3-5-min anodal tDCS protocols. The single 5-min tDCS session (A) and
the 5-3-5-min tDCS protocol (B) showed an identical involvement of intra-
cortical inhibitory and facilitatory mechanisms in the tDCS-induced excitabil-
ity modifications, irrespective of the induction of homeostatic plasticity. This
is favoring no relevant contribution of the intracortical mechanisms tested to
homeostatic plasticity. Values are means SE. Filled symbols represent
significant deviations of the double-pulse conditions from the single test pulse
amplitude with regard to each time point. ISI, interstimulus interval. P
0.05, significant difference from pre-tDCS condition.
Fig. 4. Time course of motor cortex excitability after 7-0-0, 7-1-5, 7-3-5,
7-10-5, 7-20-5, and 7-30-5 min of anodal tDCS: experiment 3. A single session
of 7 min of anodal tDCS (7-0-0 min) resulted in a significant enhancement of
MEP amplitudes, lasting for about 20 min after stimulation. If followed by
5-min tDCS with a break of 3 or 10 min (7-3-5 or 7-10-5 min), the excitability
enhancement was converted into inhibition. A break of 1 min reduced the
aftereffects of tDCS considerably (A). If the second tDCS followed the first
after a break of 20 or 30 min (7-20-5 or 7-30-5 min), excitability-enhancing
aftereffects were trendwise reestablished (B). MEP amplitudes are normalized
to baseline values. Values are means SE. Filled symbols represent signifi-
cant deviations from baseline with regard to each tDCS protocol. P 0.05,
significant difference relative to 7-0-0-min tDCS protocol.
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and combinations of tDCS, rTMS, and PAS. Moreover, ho-
meostatic effects seem to have functional relevance for motor
learning (Antal et al. 2008; Jung and Ziemann 2009).
Proposed Mechanisms of Action
There is little information on the physiological mechanisms
of homeostatic plasticity effects in humans. Many of the
mechanisms explored in animal experiments, such as changes
in factors such as tumor necrosis factor (TNF)-
, brain-derived
neurotrophic factor (BDNF), transsynaptic signaling mole-
cules, and diverse intracellular pathways (Turrigiano 2008),
work on a much longer timescale than that explored in the
present study and thus may not be relevant.
Wankerl et al. (2010) recently suggested that L-type voltage-
gated Ca
2
channels (L-VGCC) could be involved in short-
term homeostatic plasticity studied in humans based on another
noninvasive plasticity-inducing brain stimulation protocol,
namely, theta-burst stimulation. This might be similar for
tDCS, which has also been shown to induce calcium-dependent
plasticity (Nitsche et al. 2003). Their proposal was based on
two ideas: 1) that the direction [long-term potentiation (LTP)/
long-term depression (LTD)] of synaptic plasticity depends on
the magnitude and dynamics of different postsynaptic levels of
Ca
2
induced by the presynaptic input, with high levels favor
-
ing LTP and lower levels LTD; and 2) that the history of
activation of a neuron can affect the function of L-VGCC
channels such that high preceding levels of activity would
reduce their activity, whereas low levels would increase it
(Sokolova and Mody 2008; Trasande and Ramirez 2007). In
the present context, this would account for the reversal of the
effects of 5-min anodal tDCS in the 5-10-5-min protocol. Thus
the increase in neural activity produced by the initial 5-
min conditioning might have reduced the effectiveness of
L-VGCCs such that when the second 5-min stimulation was
applied, levels of Ca
2
entering postsynaptic cells would have
been less than normal and, rather than causing an LTP-like
effect (high levels of Ca
2
influx), would instead have resulted
in LTD. If this were correct, then the present results would
imply that the effects on L-VGCCs take some minutes to build
up, since immediate reversal only occurred after a 10-min
break between 5-min tDCS sessions and was less clear at 1
min, but for the 7-min preconditioning protocol, reversal was
complete after only a 3-min break immediately after condition-
ing tDCS. The theory may also be able to account for the slow
reversal of aftereffects in the anodal and cathodal 5-3-5-min
protocols. It might be that activity-dependent effects on L-
VGCCs vary between different neurons in the population
affected by tDCS. In the anodal case, we could imagine that
after 3 min, L-VGCC in some neurons had been inactivated,
whereas this was not complete in others. The latter population
might produce a dominant short-lasting facilitatory aftereffect
on corticospinal excitability, whereas the former could be
responsible for the later suppression. For cathodal stimulation,
the immediate alteration of the aftereffects could be caused by
a slight enhancement of the activation of L-VGCC by both
stimulation protocols, which together might enhance intracel-
lular Ca
2
level to a degree that induces neuroplastic excit
-
ability enhancement, and not reduction. Since this additive
effect would need no secondary mechanism, it is plausible that
it would evolve immediately after the end of stimulation. Other
mechanisms might also contribute to different temporal dy-
namics in the reduction/reversal of facilitatory and inhibitory
plasticity mechanisms, which might in the present case be
more quickly activated for inhibitory plasticity.
Although an attractive potential mechanism of action, this
concept is hypothetical at present. Future experiments should
explore the presumed physiological mechanisms more directly.
In a first approach, we studied intracortical inhibition and
facilitation by a double-pulse TMS protocol. We found no
specific effect of the repeated anodal tDCS protocol on intra-
cortical facilitation, which primarily probes the excitability of
intracortical glutamatergic neurons (Paulus et al. 2008). On
first sight, this contrasts with the proposed mechanism of
action introduced above. However, it might be argued that a
different population of glutamatergic neurons is important for
homeostatic effects from that explored using the double-stim-
ulation TMS protocol. Since TMS affects cortical neurons in a
direction-specific manner, it most probably affects only sub-
groups of neurons. Moreover, the interpretability of the intra-
cortical measures might be somewhat limited due to the fact
that we were not able to adjust test pulse amplitude after tDCS
because of temporal restrictions. Although intracortical inhibi-
tion and facilitation were not differentially affected by different
sizes of single-pulse MEP amplitudes 20 min after tDCS, it
cannot be excluded that single test pulse MEP amplitude had
an impact on the results. On the other hand, a dissociation of
the effects of TMS protocols on different parameters of cortical
excitability has also been described in other studies (Huang et
al. 2005). For exploring the suggested dependency of the
effects on specific intracellular Ca
2
concentrations directly,
animal experiments would be needed.
General Remarks
The results of the present study differ clearly from those of
another tDCS study, which involved repeated cathodal tDCS
with longer lasting stimulation protocols (9 min) that reduce
excitability for up to 1 h. Repeated application of these proto-
cols within 3–20 min led to prolongation of the inhibitory
effect, rather than reversal, whereas ISIs of 3 and 24 h induced
homeostatic effects (Monte-Silva et al. 2010). We suggest that
these longer durations of tDCS allow time for other processes
to develop, involving factors such as BDNF, TNF-
, and
others (for an overview see Turrigiano 2008) that replace the
much shorter lasting effects on VGCCs.
Some limitations of the present study should be taken into
account. Ideally, all experiments should have been conducted
in the same group of subjects, especially given the relatively
large interindividual variability of short-lasting aftereffects of
tDCS (Nitsche and Paulus 2001). Indeed, it is noteworthy that
the absolute magnitude and duration (but not the overall
direction) of the aftereffects of a single administration of 5-min
anodal stimulation differ between the experiments. Age differs
to some extent between the subexperiments and might be a
possible reason for the variability, although in all subject
groups the mean age was between 24 and 33 yr and would not
be expected to have a major effect on plasticity. Another
source of variability might have been that attention and cog-
nitive activities during the experiments differed between sub-
ject groups. Although we tried to control for this by instructing
the participants to stay awake, keep the same level of attention,
1147HOMEOSTATIC PLASTICITY BY REPEATED tDCS
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and avoid thinking about personally important things during
the experiments, interindividual differences might have been
present. In our opinion this would have resulted in an under-
estimation of the effects but not in qualitative differences,
because the general direction of the effects did not differ
between groups. The variation in baseline effects between
subject groups should be taken into consideration, particularly
when comparing the results of experiments 1 and 2, which
explore how aftereffects of stimulation depend on the inter-
tDCS interval. Thus we cannot exclude the possibility in
experiment 2 that the lack of effect in the 5-1-5-min condition
was due to the relatively low efficacy of the initial 5-min tDCS.
It should also be noted that the presence of the aftereffects of
the preconditioning tDCS during the application of the second
DC stimulation is indirect and has to be derived from the
single-tDCS stimulation conditions, because we did not mea-
sure MEP amplitudes during the break between stimulations.
We chose this procedure because we wanted to avoid the
theoretical possibility that TMS during the break affects cor-
tical excitability. In experiment 3, we compared the repeated
stimulation protocols with the 7-0-0-min stimulation protocol.
A 5-0-0-min protocol was not available in this group. Although
this might have an impact on the results, we think that this
impact should be minor, because it has been shown that the
aftereffect duration differs by only a few minutes between 5-
and 7-min tDCS (Nitsche and Paulus 2001). Moreover, taking
into account the distinction between short- and long-term
plasticity, aftereffects lasting less than 30 min, as seen after 5-
and 7-min tDCS in the present studies, are in the time range of
short-term plasticity, whereas those lasting longer than 30 min
are classified as long-lasting changes. Therefore, 5- and 7-min
tDCS are likely to induce qualitatively similar effects. Further-
more, although in the present study homeostatic effects were
induced by repeated stimulation with specific break durations,
this does not mean that a break between two stimulation
protocols is always necessary to induce homeostatic-like ef-
fects. Gentner et al. (2007) have demonstrated a reversal of the
aftereffects of continuous theta-burst stimulation in the human
motor cortex by prolongation of the stimulation duration with-
out any break. Finally, it could be argued that the second
electrode, which was positioned over the contralateral fronto-
polar cortex, might have affected motor cortex excitability.
This is improbable, however, since both areas are not anatom-
ically connected, and it has been shown that different sizes of
the frontopolar electrode, which result in functionally effective
or ineffective stimulation of this cortical area, do not affect the
impact of tDCS on motor cortex excitability (Nitsche et al.
2007b).
Conclusion
Recently, it was suggested that disorders of homeostatic
plasticity may underlie some diseases of the central nervous
system. Thus patients with writer’s cramp, a form of focal
dystonia, failed to show the normal homeostatic response
pattern in a clinical study using the protocol of Siebner et al.
(2004) (Quartarone et al. 2005). Noninvasive, painless meth-
ods like TMS and tDCS could turn out to be a promising tool
in exploring the contribution of pathologically altered meta-
plasticity to diseases of the central nervous system, which
display altered cortical excitability and activity.
Finally, the results of our study are important because a
growing number of studies are beginning to explore the pos-
sibility of treating clinical symptoms with stimulation tech-
niques in diseases known to have pathological altered cortical
excitability. For example, in stroke patients, rTMS has been
found to be a useful possible tool in neurorehabilitation (Khedr
et al. 2005; Mansur et al. 2005). Recent studies with tDCS on
patients suffering from stroke, epilepsy, depression, and central
pain (Hummel et al. 2005; Fregni et al. 2005, 2006a,b,c), as
well as models of cortical spreading depression (Liebetanz et
al. 2006), point to the possibility of influencing the course of
the disease by applying tDCS. As we have shown, the effect of
a technique that influences plastic mechanisms might, at least
under certain circumstances, depend not only on the excitabil-
ity of the motor cortex at the time the stimulation is applied but
also on its recent history, although this might not be the case
for all kinds of plasticity and might not necessarily translate
into respective behavioral or cognitive effects (Antal et al.
2008; Jung et al. 2009). This should be taken into account
when techniques such as rTMS and tDCS are used in neurore-
habilitation and treatment of diseases of the nervous system.
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the author(s).
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    • "Animal studies with a higher current density of 25 mA/cm 2 did not induce lesions in the brain tissue, meaning that limits well above those applied in humans did not result in potential adverse effects[10], thereby demonstrating that it is a safe technique. There is evidence that repeated sessions of tDCS may be associated with a longer duration of the behavioral ef- fects[11]. Monte-Silva et al.[12]demonstrated that the interval between the sessions can be critical to performance . The authors found that when an extra session of tDCS is applied for 1 hour after the first session, the effects last for a longer time (120 minutes) compared to the effect of only one or two consecutive sessions, while an extra session of tDCS applied beyond that period (that is, 3 hours) did not influence the effect of the first session. "
    [Show abstract] [Hide abstract] ABSTRACT: Background Traditional treatment for motor impairment after stroke includes medication and physical rehabilitation. The transcranial direct current stimulation associated with a standard physical therapy program may be an effective therapeutic alternative for these patients. Methods This study is a sham-controlled, double-blind, randomized clinical trial aiming to evaluate the efficacy of transcranial direct current stimulation in activities of daily living and motor function post subacute stroke. In total there will be 40 patients enrolled, diagnosed with subacute, ischemic, unilateral, non-recurring stroke. Participants will be randomized to two groups, one with active stimulation and the other with a placebo current. Patients and investigators will be blinded. Everyone will receive systematic physical therapy, based on constraint-induced movement therapy. The intervention will be applied for 10 consecutive days. Patients will undergo three functional assessments: at baseline, week 2, and week 4. Neuropsychological tests will be performed at baseline and week 4. Adverse effects will be computed at each session. On completion of the baseline measures, randomization will be conducted using random permuted blocks. The randomization will be concealed until group allocation. Discussion This study will investigate the combined effects of transcranial direct current stimulation and physical therapy on functional improvement after stroke. We tested whether the combination of these treatments is more effective than physical therapy alone when administered in the early stages after stroke. Trial registration NCT02156635 - May 30, 2014. Randomization is ongoing (40 participants randomized as of the end of December 2015).
    Full-text · Article · Dec 2016
    • "Finally, our results are also in line with the frequent observation that the direction of behavioral effects of noninvasive brain stimulation do not necessarily match the direction of presumed cortical excitability changes. Even though noninvasive inhibitory brain stimulation protocols such as 1 Hz rTMS or cTBS are usually assumed to induce a lasting " disruption " of neuronal processing in the stimulated cortical area (e.g., Huang et al., 2009), stimulation effects are complex and may vary depending on the functional state of the cortical area at the time of stimulation (Fricke et al., 2011; Fung and Robinson, 2014). For example, in a study by Pavlova et al. (2014), anodal or cathodal tDCS over the premotor cortex improved performance in a dexterity-demanding motor task, depending on perceived task difficulty, and specific performance features. "
    [Show abstract] [Hide abstract] ABSTRACT: The purpose of this study was to determine whether exposure to specific auditory sequences leads to the induction of new motor memories and to investigate the role of the dorsal premotor cortex (dPMC) in this crossmodal learning process. Fifty-two young healthy non-musicians were familiarized with the sound to key-press mapping on a computer keyboard and tested on their baseline motor performance. Each participant received subsequently either continuous theta burst stimulation (cTBS) or sham stimulation over the dPMC and was then asked to remember a 12-note melody without moving. For half of the participants, the contour of the melody memorized was congruent to a subsequently performed, but never practiced, finger movement sequence (Congruent group). For the other half, the melody memorized was incongruent to the subsequent finger movement sequence (Incongruent group). Hearing a congruent melody led to significantly faster performance of a motor sequence immediately thereafter compared to hearing an incongruent melody. In addition, cTBS speeded up motor performance in both groups, possibly by relieving motor consolidation from interference by the declarative melody memorization task. Our findings substantiate recent evidence that exposure to a movement-related tone sequence can induce specific, crossmodal encoding of a movement sequence representation. They further suggest that cTBS over the dPMC may enhance early offline procedural motor skill consolidation in cognitive states where motor consolidation would normally be disturbed by concurrent declarative memory processes. These findings may contribute to a better understanding of auditory-motor system interactions and have implications for the development of new motor rehabilitation approaches using sound and non-invasive brain stimulation as neuromodulatory tools.
    Full-text · Article · May 2016
    • "This problem can be circumvented by establishing a first session that is not included in the terminal data analysis. In multiple session approaches, for short-term plasticity effects (5 or 7 min stimulation) an inter-session interval of one hour is sufficient (Nitsche et al. 2005; Fricke et al. 2011). For long-term plasticity effects, an interval of one week should avoid interferences, whereas a 24 h break is insufficient (Monte-Silva et al. 2010). "
    [Show abstract] [Hide abstract] ABSTRACT: Transcranial electrical stimulation (tES), including transcranial direct and alternating current stimulation (tDCS, tACS) are non-invasive brain stimulation techniques increasingly used for modulation of central nervous system excitability in humans. Here we address methodological issues required for tES application. This review covers technical aspects of tES, as well as applications like exploration of brain physiology, modelling approaches, tES in cognitive neurosciences, and interventional approaches. It aims to help the reader to appropriately design and conduct studies involving these brain stimulation techniques, understand limitations and avoid shortcomings, which might hamper the scientific rigor and potential applications in the clinical domain.
    Full-text · Article · Nov 2015
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