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Towards unravelling task-related modulations of
neuroplastic changes induced in the human motor cortex
Andrea Antal,
1
Daniella Terney,
1,2
Csaba Poreisz
1
and Walter Paulus
1
1
Department of Clinical Neurophysiology, Georg-August University of Go
¨ttingen, Robert Koch Straße 40, 37075 Go
¨ttingen,
Germany
2
Department of Neurology, University of Szeged, Szeged, Hungary
Keywords: motor contraction, motor evoked potential, transcranial direct current stimulation, transcranial magnetic stimulation
Abstract
Stimulation with weak electrical direct currents has been shown to be capable of inducing stimulation-polarity-dependent prolonged
diminutions or elevations of cortical excitability, most probably elicited by a hyper- or depolarization of resting membrane potentials.
The aim of the present study was to test if cognitive task and motor exercise practiced during the stimulation are able to modify
transcranial direct current stimulation-induced plasticity in the left primary motor cortex in 12 healthy subjects. Motor evoked
potentials were recorded before and after 10 min of anodal and cathodal transcranial direct current stimulation. In Experiment 1,
subjects were required to sit passively during the stimulation, in Experiment 2 the subject’s attention was directed towards a cognitive
test and in Experiment 3 subjects were instructed to push a ball in their right hand. Both the cognitive task and motor exercise
modified transcranial direct current stimulation-induced plasticity; when performing the cognitive task during stimulation the motor
cortex excitability was lower after anodal stimulation and higher after cathodal stimulation, compared with the passive condition.
When performing the motor exercise, the motor cortex excitability was lower after both anodal and cathodal stimulation, compared
with the passive condition. Our results show that transcranial direct current stimulation-induced plasticity is highly dependent on the
state of the subject during stimulation.
Introduction
Transcranial direct current stimulation (tDCS) appears to be a
promising tool in neuroplasticity research with perspectives in clinical
neurophysiology (Fregni & Pascual-Leone, 2007). Its effect is closely
related to modulation of cortical excitability and activity, which are
key mechanisms for learning and memory processing (Paulus, 2004).
The primary effect of tDCS is a neuronal de- or hyperpolarization of
membrane potentials (Creutzfeldt et al., 1962; Bindman et al., 1964),
whereby the induced after-effects depend on N-methyl-d-aspartate
(NMDA) receptor efficacy changes (Liebetanz et al., 2002). There is
also evidence for both GABAergic (Nitsche et al., 2004a) and
dopaminergic modulation of tDCS-induced effects (Nitsche et al.,
2006). The most common way to evaluate cortical excitability changes
is by applying transcranial magnetic stimulation (TMS) to the motor
cortex, as it allows reproducible and quantifiable effects through the
analysis of motor evoked potentials (MEPs). Anodal stimulation
increases the amplitude of MEPs and cathodal stimulation decreases
them (Nitsche & Paulus, 2000). The relevant stimulation parameters
encompass the polarity, the combination of current strength, size of the
stimulated area and duration of the stimulation (Agnew & McCreery,
1987) and are considered to be safe by several studies (Nitsche et al.,
2003; Iyer et al., 2005; Poreisz et al., 2007).
The aim of this study was to investigate whether a mental or motor
activity performed during stimulation can modify the efficacy of
tDCS. Therefore, the subjects were required to pay attention and fill
out a cognitive task or push a ball for the duration of the anodal or
cathodal tDCS.
A recent study applied a paired associative stimulation (PAS)
protocol (Stefan et al., 2004). PAS-induced changes of cortical
excitability, similarly to tDCS-induced plasticity, share a number of
physiological properties with LTP (for a review see Classen et al.,
2004). PAS-induced plasticity was completely blocked when the
subject’s attention was directed toward a cognitive test.
With regard to motor task, several previous studies have examined
the effect of motor exercise and related muscle fatigue on corticospinal
activity. Motor fatigue is defined as a reduction in the force generated
by a muscle or a group of muscles after sustained or repeated
contraction (Merton, 1954). In recent years the central component of
fatigue was extensively investigated using TMS (Gandevia, 1996;
Samii et al., 1996; Sacco et al., 1997, 2000; Zijdewind et al., 2000)
and it was shown that, immediately after a non-exhaustive exercise,
the amplitude of TMS-induced MEPs increases (Balbi et al., 2002). If
the exercise is repeated until muscle fatigue, a MEP amplitude
decrease can be observed (Brasil-Neto et al., 1994).
Furthermore, attentional and cognitive deficits and involuntary
motor contractions are frequent symptoms of many neurological and
psychiatric disorders such as Alzheimer’s disease (Claus & Mohr,
1996), Huntington’s disease (Sprengelmeyer et al., 1995; Finke et al.,
2006) and Parkinson’s disease (Claus & Mohr, 1996; Braak et al.,
2005). If the efficacy of tDCS in inducing motor cortical excitability is
a task-related parameter, the magnitude of plasticity might be variable
or even completely blocked in patients compared with healthy
subjects.
Correspondence: Dr Andrea Antal, as above.
E-mail: AAntal@gwdg.de
Received 1 June 2007, revised 12 September 2007, accepted 18 September 2007
European Journal of Neuroscience, Vol. 26, pp. 2687–2691, 2007 doi:10.1111/j.1460-9568.2007.05896.x
ªThe Authors (2007). Journal Compilation ªFederation of European Neuroscience Societies and Blackwell Publishing Ltd
Materials and methods
Subjects
Twelve healthy volunteers (six males; aged between 21 and 26 years,
mean age 22.75 ± 1.36 years) were informed about all aspects of the
experiments and all signed an informed consent form. All were
consistent right-handers according to the 10-item version of the
Edinburgh Handedness Inventory (Oldfield, 1971). We conformed to
the Declaration of Helsinki and the experimental protocol was
approved by the Ethics Committee of the University of Go¨ttingen.
None of the subjects suffered from any neurological or psychological
disorders and none had metallic implants ⁄implanted electric devices
or took any medication regularly.
Transcranial direct current stimulation
Direct currents were transferred via a pair of saline-soaked surface
sponge electrodes (5 ·7 cm) fixed to the scalp and delivered by a
specially developed battery-driven current stimulator (NeuroConn
GmbH, Ilmenau, Germany). The motor-cortical electrode was placed
over the representational field of the right first dorsal interosseus
muscle (FDI) as identified by TMS, whereas the other electrode was
located contralaterally above the right eyebrow. The electrodes were
orientated approximately parallel to the central sulcus and the
eyebrow. This montage has been proven to be the most effective for
modulating motor cortex excitability (Nitsche & Paulus, 2000; Nitsche
et al., 2003). The type of stimulation (anodal or cathodal) refers to the
polarity of the electrode above the motor cortex. Subjects were blinded
as to the polarity of tDCS. The current was applied for 10 min with an
intensity of 1.0 mA. The fade-in ⁄fade-out time was 8 s.
Transcranial magnetic stimulation
To detect current-driven changes of excitability, MEPs of the right FDI
were recorded following stimulation of its motor-cortical representa-
tional field by single-pulse TMS. These were induced using a
Magstim 200 magnetic stimulator (Magstim Company, Whiteland,
Wales, UK) and a figure-of-eight standard double magnetic coil
(diameter of one winding, 70 mm; peak magnetic field, 2.2 T; average
inductance, 16.35 lH). The coil was held tangentially to the skull,
with the handle pointing backwards and laterally at 45!from the
midline, resulting in a posterior–anterior direction of current flow in
the brain. The optimal position was defined as the site where
stimulation resulted consistently in the largest MEP. The site was
marked with a skin marker to ensure that the coil was held in the
correct position throughout the experimental sessions. Surface EMG
was recorded from the right FDI by use of an Ag ⁄AgCl electrode in a
belly tendon montage. The signals were amplified and filtered
(2 Hz)3 kHz; maximal signal frequency, 1 kHz; sampling rate,
5 kHz), digitized with a micro 1401 AD converter (Cambridge
Electronic Design, Cambridge, UK) and recorded by a computer
using Signal software (Cambridge Electronic Design, version 2.13).
Data were analysed offline on a personal computer. Complete muscle
relaxation was controlled though auditory and visual feedback of
EMG activity. The intensity of the stimulator output was adjusted for
baseline recording so that the average stimulus led to an MEP of
!1 mV (SI
1mV
).
Experimental procedures
The six experimental sessions were conducted in a repeated measure-
ment design using a randomized order, with a break of at least 4 days
between each session. The subjects were seated in a reclining chair.
First, the left motor-cortical representational field of the right FDI was
identified using TMS (coil position that leads to the largest MEPs of
FDI). After determining the resting and active motor thresholds, the
subjects were asked to relax for at least 5 min. A baseline of TMS-
evoked MEPs (50 stimuli) was then recorded at a time constant of
4 ± 0.04 s. Afterwards, one direct current stimulation electrode, in an
anodal or cathodal orientation, was fixed at the representational field
of the right FDI and the other was fixed at the contralateral forehead
above the orbita.
During anodal and cathodal stimulation, subjects were passively
sitting during the stimulation (Experiment 1), had their attention
directed towards a cognitive test (Experiment 2) or were instructed to
push a ball in their right hand (Experiment 3). After termination of
tDCS, a 5 min break was inserted into the protocol as the pilot
experiments indicated that many of the subjects were not able to relax
after the termination of the motor exercise. After this break 25 MEPs
were recorded at a time constant of 4 ± 0.04 s every fifth minute up to
30 min (in the case of 12 subjects) and then every 15 min up to
90 min (in the case of six subjects).
During the stimulation in Experiment 2 the subjects were required
to fill out a cognitive test that was presented on a computer monitor.
The subjects had to push a suitable button with their right index finger
in order to give the correct answer. The test was presented in German
and downloaded from a commercial intelligence test homepage. To
avoid any training effect we used a cognitive task with a different
series of questions during the anodal and cathodal tDCS. The
questions were on a variety of subjects, i.e. mathematics, literature,
geography and history, and were all of different lengths; therefore, a
direct comparison of the results was not possible (the number of
responses was measured instead of reaction time). However, the
accuracies and the subjective reports of the subject were documented
after stimulation.
In Experiment 3, the subjects were instructed to push a ball (8 cm
diameter) in their right hand. The ball was connected to a display
where the actual values related to pressure were quantified. Before the
stimulation session the subjects were asked to push the ball as hard as
possible. During the tDCS session subjects had to push the ball to half-
maximal contraction as previously shown.
Statistical analysis
Repeated measures anova [EXPERIMENT (passive vs. cogni-
tive ⁄motor) ·TIME (before, 5, 10, 15, 20, 25 and 30 min after
stimulation] was used to compare different task conditions during
anodal or cathodal stimulation. Effects were considered significant if
P< 0.05. Bonferroni corrected t-test was used for post-hoc compar-
ison. Student’s t-test was used to compare the motor thresholds
(resting motor threshold, active motor threshold and SI
1mV
) between
experimental sessions. All data are given as means + SEM.
Results
All of the subjects tolerated tDCS and had no side-effects during or
after the stimulation.
Active motor threshold, resting motor threshold and SI
1mV
baseline
values were compared between anodal and cathodal conditions within
the passive condition, and concerning the cognitive and motor tasks
using Student’s t-test. There was no significant difference between
anodal and cathodal stimulation in any of the measurements at
baseline.
2688 A. Antal et al.
ªThe Authors (2007). Journal Compilation ªFederation of European Neuroscience Societies and Blackwell Publishing Ltd
European Journal of Neuroscience,26, 2687–2691
A subjective decline in performance was reported by two of the
subjects in the case of anodal tDCS in Experiment 2.
Anodal stimulation
Following anodal stimulation the amplitude of the MEPs was
increased in the passive condition, slightly decreased in the cognitive
condition and markedly reduced in the motor condition. When the
amplitude of the MEPs was compared with regard to the passive
condition and cognitive task before and after anodal stimulation,
repeated measures anova revealed a main effect of EXPERIMENT
(F
1,11
¼9.25, P¼0.01) but TIME (F
6,66
¼1.89, P¼0.09) and the
interaction between EXPERIMENT and TIME were not significant
(F
6,66
¼1.55, P¼0.17). When the amplitude of the MEPs was
compared with regard to the passive condition and motor task,
repeated measures anova revealed a main effect of EXPERIMENT
(F
1,11
¼39.46, P< 0.0000) but TIME was not significant
(F
6,66
¼0.9, P¼0.49). The interaction between EXPERIMENT
and TIME was significant (F
6,66
¼6.77, P< 0.0001). The post-hoc
test revealed that, after anodal stimulation in the passive condition,
significantly increased MEP amplitudes were observed up to 25 min
(P< 0.0001) (Fig. 1).
Cathodal stimulation
Following cathodal stimulation the amplitude of the MEPs was
decreased in the passive condition, slightly increased in the cognitive
condition and markedly diminished in the motor condition. When the
amplitude of the MEPs was compared with regard to the passive
condition and cognitive task before and after cathodal stimulation,
repeated measures anova revealed a main effect of EXPERIMENT
(F
1,11
¼52.44, P< 0.0000) and TIME (F
6,66
¼3.57, P¼0.004).
The interaction between EXPERIMENT and TIME was also
significant (F
6,66
¼4.23, P¼0.001). The post-hoc test revealed
that, after cathodal stimulation in the passive condition, significantly
increased MEP amplitudes were observed up to 30 min (P< 0.03)
(Fig. 1). When the amplitude of the MEPs was compared with regard
to the passive condition and motor task, repeated measures anova
revealed a main effect of EXPERIMENT (F
1,11
¼12.59, P< 0.04)
and TIME (F
6,66
¼20.09, P< 0.0000). The interaction between
EXPERIMENT and TIME was not significant (F
6,66
¼1.69,
P¼0.13) (Fig. 1).
Discussion
To our knowledge, the present study is the first to show that neuronal
plasticity induced in the human primary motor cortex by tDCS is
modified by paying attention to mental activity and by repeated
contractions of the target muscle during the stimulation. In the passive
condition, anodal stimulation increased whereas cathodal stimulation
decreased the amplitude of MEPs, as described in many previous
studies (Nitsche & Paulus, 2000, 2001; Lang et al., 2004). However,
when the subjects were required to perform a cognitive test during
stimulation, the MEP amplitudes were slightly increased after cathodal
stimulation or were non-significantly decreased after anodal stimula-
tion. Voluntary motor contraction during anodal and cathodal stim-
ulation resulted in a decrease in MEP amplitudes, probably due to
muscle fatigue as described by many previous studies (Samii et al.,
1996; Sacco et al., 1997, 2000; Zijdewind et al., 2000), independent of
the polarity of the stimulation.
A recent study by Stefan et al. (2004) applied a similar paradigm,
but using a different method, in order to describe attentional
Fig. 1. Effect of 10 min anodal and cathodal stimulation on motor evoked potential (MEP) amplitudes. During the stimulation, the subjects were in a passive
state (sitting), were required to complete a cognitive test presented on a computer monitor or had to push a ball with their right hand. The figure shows mean
amplitudes and their SEMs up to 30 min (including all subjects, n¼12) and between 45 and 90 min (including six subjects). tDCS, transcranial direct current
stimulation.
Effect of tDCS is modified by mental activity and exercise 2689
ªThe Authors (2007). Journal Compilation ªFederation of European Neuroscience Societies and Blackwell Publishing Ltd
European Journal of Neuroscience,26, 2687–2691
modulation of neuroplasticity. PAS refers to a paradigm consisting of
slow-rate repetitive low-frequency median nerve stimulation com-
bined with TMS over the contralateral M1. Its principles of design
were shaped after associative LTP in experimental animals, a
mechanism likely to be relevant for learning and memory (for a
review see Classen et al., 2004). In the study by Stefan et al. (2004)
PAS-induced plasticity was maximal when the subjects viewed their
hand during stimulation and was reduced when the subjects only felt
their hand. PAS failed to induce plasticity when the attention was
directed towards the non-target hand or when a cognitive task was
presented during stimulation.
The reduction of tDCS-induced plasticity during the cognitive task
can be explained by previous neurophysiological (Motter, 1993) and
imaging (Corbetta et al., 1990; Rowe et al., 2002) studies. These
studies imply that cortical areas that are not involved in the processing
of an attended task are deactivated. The processes of deactivation
probably interfered with the neurophysiological processes (e.g.
cortical inhibition) underlying tDCS-induced neuroplasticity. It should
also be considered that tDCS was applied subthreshold, similarly to
many previous studies, and higher current densities might result in
different outcomes.
After the motor task a decline in the MEP amplitudes was observed
after both types of stimulation, possibly due to the exercise and related
muscle fatigue. Brasil-Neto et al. (1993) first observed that post-
exercise MEPs were decreased when compared with pre-exercise
MEPs, after an exhausting forearm exercise. Later studies have
supported this result and additionally showed that post-exercise MEP
reduction is often preceded by a short initial increase in MEP
amplitude, called post-exercise facilitation, probably mirroring the
neurotransmitter mobilization and depletion (Brasil-Neto et al., 1994;
McKay et al., 1995; Liepert et al., 1996). In our study we observed
only a decrease after exercise and stimulation; however, we requested
that the subjects have a 5 min break between the end of stimulation
and the first recording session, in order to avoid spontaneous muscle
contractions immediately after the termination of the voluntary
contractions. As we did not observe any significant difference between
cathodal and anodal stimulation, we suppose that the stimulation had
no effect during this condition. However, a recent study has reported
that anodal tDCS over the right motor areas resulted in an improved
endurance time for a submaximal isometric contraction of the left
elbow flexors, whereas the cathodal or no-stimulation condition did
not produce such an effect (Cogiamanian et al., 2007). In the same
study it was also observed that, after the end of anodal stimulation, the
amplitude of MEPs during a slight isometric biceps brachialis
contraction (about 5% of the maximal voluntary contraction) increased
significantly compared with the before-stimulation values. According
to these results, anodal stimulation is able to modify human
neuromuscular fatigue. However, in our study it is difficult to
distinguish the reduction of cortical excitability due to muscle exercise
from the effect of stimulation as we employed no sham condition.
Furthermore, in the present study tDCS was applied during motor
exercise (not during rest) and a different electrode position was used
(left M1, right orbit vs. right M1, right shoulder). These technical
differences might give rise to different results. Nevertheless, the
purpose of our study was to investigate the effect of motor exercise on
tDCS-induced neuroplasticity and not the effect of tDCS on fatigue.
In our study both the cognitive and motor tasks interacted with the
tDCS protocol. The effect of tDCS is intracortical (Nitsche et al.,
2005). Whereas the effects during stimulation were probably due to
the direct-current-induced shifts of resting membrane potential, the
induction of longer lasting after-effects could well differ from these.
Nevertheless, recent pharmacological studies proved that the after-
effects of tDCS are NMDA receptor dependent (Liebetanz et al.,
2002). It is known that long-lasting NMDA-receptor-dependent
cortical excitability and activity shifts are involved in neuroplastic
modification. NMDA receptor and intracellular sigma 1 receptor
blocker dextromethorphan intake prevented both anodal and cathodal
tDCS-induced after-effects, demonstrating that dextromethorphan
critically interferes with the functionality of tDCS irrespective of the
polarity of direct current stimulation (Liebetanz et al., 2002; Nitsche
et al., 2004b). d-cycloserine, a partial NMDA agonist, selectively
potentiated the duration of motor cortical excitability enhancements
induced by anodal tDCS (Nitsche et al., 2004b). Additional receptors
are also involved. Administration of the GABA(A) receptor agonist
lorazepam resulted in a delayed but then enhanced and prolonged
anodal tDCS-induced excitability elevation (Nitsche et al., 2004a). In
addition, dopaminergic mechanisms can stabilize these processes. In a
recent study, the enhancement of D2, and to a lesser degree of D1,
receptors by pergolide consolidated tDCS-generated excitability
diminution up until the morning post-stimulation (Nitsche et al.,
2006).
In the present study we have proven that the effectiveness of tDCS
in inducing motor cortical excitability changes depends on the
cognitive state of the subjects and the activity level of the examined
muscle induced by motor contraction. The limitation of our investi-
gation is that results from a study employing healthy subjects cannot
be directly transferable to clinical settings. Nevertheless, attentional
and cognitive problems occur in older individuals and patients with
varying neurological disorders more frequently than healthy subjects
(Sprengelmeyer et al., 1995; Claus & Mohr, 1996; Adler, 2005; Braak
et al., 2005; Finke et al., 2006). Similarly, involuntary motor
contractions and tremor are frequent symptoms of many neurological
and psychiatric disorders (Marsden et al., 1983; Benecke et al., 1987;
Rondot, 1991). The question that emerges is whether tDCS can be
targeted accurately enough concerning the stimulation parameters to
achieve a neuroplastic effect in these disorders.
Acknowledgements
This study was funded by the Bernstein Center for Computational Neurosci-
ence (01GQ0432) (A.A.) and the Rose Foundation (C.P.). We would like to
thank Leila Chaieb for the English corrections.
Abbreviations
FDI, first dorsal interosseus muscle; MEP, motor evoked potential; NMDA,
N-methyl-d-aspartate; PAS, paired associative stimulation; tDCS, transcranial
direct current stimulation; TMS, transcranial magnetic stimulation.
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ªThe Authors (2007). Journal Compilation ªFederation of European Neuroscience Societies and Blackwell Publishing Ltd
European Journal of Neuroscience,26, 2687–2691
