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Towards unraveling task-related modulations of neuroplastic changes induced in the human motor cortex

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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.
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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Effect of tDCS is modified by mental activity and exercise 2691
ªThe Authors (2007). Journal Compilation ªFederation of European Neuroscience Societies and Blackwell Publishing Ltd
European Journal of Neuroscience,26, 2687–2691
... During continuous stimulation, for 10e20 min, any number of different behaviours may be performed alongside the specific task that is the 'target' of stimulation. The concatenation of all these behaviours under the same stimulation conditions may lead to changes in excitation levels in multiple cortical circuits that confound the results, contributing to some of the conflicting findings [40]. In contrast, event-related TDCS may selectively modulate only those circuits and taskrelated synapses that are contemporaneously active and undergoing concurrent plasticity [16,41]. ...
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Background There is a current discord between the foundational theories underpinning motor learning and how we currently apply transcranial direct current stimulation (TDCS): the former is dependent on tight coupling of events while the latter is conducted with very low temporal resolution. Objective Here we aimed to investigate the temporal specificity of stimulation by applying TDCS in short epochs, and coincidentally with movement, during a motor adaptation task. Methods Participants simultaneously adapted a reaching movement to two opposing velocity-dependent force-fields (clockwise and counter-clockwise), distinguished by a contextual leftward or rightward shift in the task display and cursor location respectively. Brief bouts (<3 s) of event-related TDCS (er-TDCS) were applied over M1 or the cerebellum during movements for only one of these learning contexts. Results We show that when short duration stimulation is applied to the cerebellum and yoked to movement, only those reaching movements performed simultaneously with stimulation are selectively enhanced, whilst similar and interleaved movements are left unaffected. We found no evidence of improved adaptation following M1 er-TDCS, as participants displayed equivalent levels of error during both stimulated and unstimulated movements. Similarly, participants in the sham stimulation group adapted comparably during left and right-shift trials. Conclusions It is proposed that the coupling of cerebellar stimulation and movement influences timing-dependent (i.e., Hebbian-like) mechanisms of plasticity to facilitate enhanced learning in the stimulated context.
... It is commonly assumed that tDCS electric current facilitates cortical areas under the anode electrode and consequently that this promotes behaviour associated to those brain regions, whereas a negative 'cathodal' current, with the electrodes reversed, inhibits behaviours relative to the same cortical target (Antal, Terney, Poreisz, & Paulus, 2007;Furubayashi et al., 2008;Nitsche et al., 2008Nitsche et al., , 2005Nitsche & Paulus, 2000;Priori, Berardelli, Rona, Accornero, & Manfredi, 1998;Uy & Ridding, 2003). In other words, depending on stimulation polarity, membrane potentials may depolarise and increase the probability of eliciting action potentials or hyperpolarise and decrease the likelihood of eliciting action potentials (see Figure 1.3; Nitsche & Paulus, 2000), which lead to the aforementioned facilitatory or inhibitory effects, respectively (Dissanayaka et al., 2017;Nitsche et al., 2008;Paulus et al., 2013;Stagg & Nitsche, 2011). ...
Thesis
The ability of transcranial direct current stimulation (tDCS) to modulate brain activity has vast scientific and therapeutic potential, however, its effects are often variable which limit its utility. Both current flow direction and variance in electric field intensities reaching a cortical target may be vital sources of the variable tDCS effects on neuroplastic change. Controlling for these and exploring the subsequent effects on corticospinal excitability is the aim of this thesis. I here attempted to optimise the delivery of tDCS application by investigating the controlled application of current flow direction and whether through the use of current flow models, we can deliver comparable electric fields with reduced variability across differential montages. To assess whether current flow models are useful, I further investigated if dose-control translates to more consistent physiological outcomes. I demonstrate, firstly, that different current flow directions did not differentially affect the two banks of the central sulcus. Secondly, with the use of dose-control, high-definition tDCS (HD-tDCS) remains focally more advantageous, even with the delivery of comparable electric field intensity and variability as posterior-anterior tDCS (PA-tDCS) to a cortical region. Thirdly, dose-controlled tDCS does not translate to reduced physiological variability. Together, the work presented here suggests that current flow models are useful for informing dose-controlled protocols and montage comparisons for improved tDCS delivery, however, controlling for anatomical differences in the delivery of electric fields to a target is not sufficient to reduce the variability of tDCS effects in physiology. Thus, the methodology for optimised tDCS delivery remains a subject for further improvement and investigation. Advancements in this field may lead to a trusted methodology assisting stroke survivors with a more effective and efficient motor recovery journey.
... In tDCS research, the distinction between online and offline application has important implications, with some studies demonstrating that the direction of effect-an improvement versus an impairment of performance-can depend on whether offline or online stimulation is being applied. (Antal et al., 2007;Bortoletto et al., 2015;Grasso et al., 2020;Martin et al., 2014;Stagg et al., 2011). In an important example, a functional connectivity analysis was conducted while anodal tDCS was applied to the right IFG (with a similar extracephalic placement of the cathode as the current study), both during a task and at rest. ...
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Objectives Mindfulness-Based Relapse Prevention (MBRP) and transcranial direct current stimulation (tDCS) have each demonstrated efficacy in improving outcomes in those with alcohol use disorder (AUD); however, a recent study that combined MBRP with tDCS found tDCS provided no additional benefit to MBRP for AUD. Differences in treatment adherence between active versus sham tDCS groups may have contributed to this result. The current study examined whether treatment adherence interacted with tDCS condition in predicting post-treatment mindfulness and craving.Methods This study was a secondary data analysis from a randomized sham-controlled trial comparing MBRP paired with tDCS. Linear regression analyses were conducted examining the interaction between tDCS condition and two measures of treatment adherence (i.e., number of groups attended, number of tDCS administrations) on post-treatment mindfulness and craving.ResultsThere was no effect of treatment adherence by tDCS condition in predicting mindfulness; however, the interaction between treatment adherence and tDCS condition significantly predicted post-treatment craving. There was a significant negative association between treatment adherence and post-treatment craving in the sham group, but there was no association in the active tDCS group.ConclusionsMBRP coupled with sham stimulation led to significant reductions in self-reported craving when patients attended more sessions and received a greater number of sham tDCS administrations, while no relationship was observed between treatment adherence and craving among those who received active tDCS. This result provides tentative evidence that, rather than improve the effects of MBRP on craving, this active tDCS protocol provides no additional benefit to MBRP in reducing craving.
... Consider the simple case of applying tES either during task performance or during rest. Clearly, brain activity in these two states differs, and tES application will result in a different response: applying tES either before or during movement can result in opposing effects [66][67][68][69], though CFMs would prescribe an identical stimulation protocol in either case. ...
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Purpose of Review Transcranial electrical stimulation (tES) is used to non-invasively modulate brain activity in health and disease. Current flow modeling (CFM) provides estimates of where and how much electrical current is delivered to in the brain during tES. It therefore holds promise as a method to reduce commonplace variability in tES delivery and, in turn, the outcomes of stimulation. However, the adoption of CFM has not yet been widespread and its impact on tES outcome variability is unclear. Here, we discuss the potential barriers to effective, practical CFM-informed tES use. Recent Findings CFM has progressed from models based on concentric spheres to gyri-precise head models derived from individual MRI scans. Users can now estimate the intensity of electrical fields (E-fields), their spatial extent, and the direction of current flow in a target brain region during tES. Here. we consider the multi-dimensional challenge of implementing CFM to optimise stimulation dose: this requires informed decisions to prioritise E-field characteristics most likely to result in desired stimulation outcomes, though the physiological consequences of the modelled current flow are often unknown. Second, we address the issue of a disconnect between predictions of E-field characteristics provided by CFMs and predictions of the physiological consequences of stimulation which CFMs are not designed to address. Third, we discuss how ongoing development of CFM in conjunction with other modelling approaches could overcome these challenges while maintaining accessibility for widespread use. Summary The increasing complexity and sophistication of CFM is a mandatory step towards dose control and precise, individualised delivery of tES. However, it also risks counteracting the appeal of tES as a straightforward, cost-effective tool for neuromodulation, particularly in clinical settings.
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Background Fatigue and emotional distress rank high among self‐reported unmet needs in life after stroke. Transcranial direct current stimulation (tDCS) may have the potential to alleviate these symptoms for some patients, but the acceptability and effects for chronic stroke survivors need to be explored in randomized controlled trials. Methods Using a randomized sham‐controlled parallel design, we evaluated whether six sessions of 1 mA tDCS (anodal over F3, cathodal over O2) combined with computerized cognitive training reduced self‐reported symptoms of fatigue and depression. Among the 74 chronic stroke patients enrolled at baseline, 54 patients completed the intervention. Measures of fatigue and depression were collected at five time points spanning a 2 months period. Results While symptoms of fatigue and depression were reduced during the course of the intervention, Bayesian analyses provided evidence for no added beneficial effect of tDCS. Less severe baseline symptoms were associated with higher performance improvement in select cognitive tasks, and study withdrawal was higher in patients with more fatigue and younger age. Time‐resolved symptom analyses by a network approach suggested higher centrality of fatigue items (except item 1 and 2) than depression items. Conclusion The results reveal no add‐on effect of tDCS on fatigue or depression but support the notion of fatigue as a relevant clinical symptom with possible implications for treatment adherence and response.
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Attempts to enhance human memory and learning ability have a long tradition in science. This topic has recently gained substantial attention because of the increasing percentage of older individuals worldwide and the predicted rise of age-associated cognitive decline in brain functions. Transcranial brain stimulation methods, such as transcranial magnetic (TMS) and transcranial electric (tES) stimulation, have been extensively used in an effort to improve cognitive functions in humans. Here we summarize the available data on low-intensity tES for this purpose, in comparison to repetitive TMS and some pharmacological agents, such as caffeine and nicotine. There is no single area in the brain stimulation field in which only positive outcomes have been reported. For self-directed tES devices, how to restrict variability with regard to efficacy is an essential aspect of device design and function. As with any technique, reproducible outcomes depend on the equipment and how well this is matched to the experience and skill of the operator. For self-administered non-invasive brain stimulation, this requires device designs that rigorously incorporate human operator factors. The wide parameter space of non-invasive brain stimulation, including dose (e.g., duration, intensity (current density), number of repetitions), inclusion/exclusion (e.g., subject’s age), and homeostatic effects, administration of tasks before and during stimulation, and, most importantly, placebo or nocebo effects, have to be taken into account. The outcomes of stimulation are expected to depend on these parameters and should be strictly controlled. The consensus among experts is that low-intensity tES is safe as long as tested and accepted protocols (including, for example, dose, inclusion/exclusion) are followed and devices are used which follow established engineering risk-management procedures. Devices and protocols that allow stimulation outside these parameters cannot claim to be “safe” where they are applying stimulation beyond that examined in published studies that also investigated potential side effects. Brain stimulation devices marketed for consumer use are distinct from medical devices because they do not make medical claims and are therefore not necessarily subject to the same level of regulation as medical devices (i.e., by government agencies tasked with regulating medical devices). Manufacturers must follow ethical and best practices in marketing tES stimulators, including not misleading users by referencing effects from human trials using devices and protocols not similar to theirs.
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Invasive and non-invasive brain stimulation methods are widely used in neuroscience to establish causal relationships between distinct brain regions and the sensory, cognitive and motor functions they subserve. When combined with concurrent brain imaging, such stimulation methods can reveal patterns of neuronal activity responsible for regulating simple and complex behaviours at the level of local circuits and across widespread networks. Understanding how fluctuations in physiological states and task demands might influence the effects of brain stimulation on neural activity and behaviour is at the heart of how we use these tools to understand cognition. Here we review the concept of such ‘state-dependent’ changes in brain activity in response to neural stimulation, and consider examples from research on altered states of consciousness (for example, sleep and anaesthesia) and from task-based manipulations of selective attention and working memory. We relate relevant findings from non-invasive methods used in humans to those obtained from direct electrical and optogenetic stimulation of neuronal ensembles in animal models. Given the widespread use of brain stimulation as a research tool in the laboratory and as a means of augmenting or restoring brain function, consideration of the influence of changing physiological and cognitive states is crucial for increasing the reliability of these interventions. In this Review, Bradley, Nydam, Dux and Mattingley explore state-dependent variations in brain activity and behaviour with brain stimulation. They focus on transcranial magnetic stimulation and transcranial electrical stimulation and several domains — conscious state, attention and working memory.
Chapter
Activity-dependent synaptic plasticity is the main theoretical framework to explain mechanisms of learning and memory. Synaptic plasticity can be explored experimentally in animals through various standardized protocols for eliciting long-term potentiation and long-term depression in hippocampal and cortical slices. In humans, several non-invasive protocols of repetitive transcranial magnetic stimulation and transcranial direct current stimulation have been designed and applied to probe synaptic plasticity in the primary motor cortex, as reflected by long-term changes in motor evoked potential amplitudes. These protocols mimic those normally used in animal studies for assessing long-term potentiation and long-term depression. In this chapter, we first discuss the physiologic basis of theta-burst stimulation, paired associative stimulation, and transcranial direct current stimulation. We describe the current biophysical and theoretical models underlying the molecular mechanisms of synaptic plasticity and metaplasticity, defined as activity-dependent changes in neural functions that modulate subsequent synaptic plasticity such as long-term potentiation (LTP) and long-term depression (LTD), in the human motor cortex including calcium-dependent plasticity, spike-timing-dependent plasticity, the role of N-methyl-d-aspartate-related transmission and gamma-aminobutyric-acid interneuronal activity. We also review the putative microcircuits responsible for synaptic plasticity in the human motor cortex. We critically readdress the issue of variability in studies investigating synaptic plasticity and propose available solutions. Finally, we speculate about the utility of future studies with more advanced experimental approaches.
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Fatigue-associated changes in the excitability of central motor mechanisms were investigated using transcranial magnetic stimulation (TMS) of the motor cortex. Test stimuli were applied before, during and after a voluntary fatigue test of the first dorsal interosseus muscle (FDI). Subjects were required to maintain 50% of their maximum voluntary force (MVC) for at least 2 min (1/2-MVC test) and electromyographic (EMG) reactions of FDI were measured with surface electrodes. Prior to the test, TMS pulses of 70% maximum output (about 1.4 T) produced muscle-evoked potentials (MEPs) of widely different amplitudes in different subjects, ranging from 13% to 55% of the maximum compound action potential (M-wave) evoked by ulnar nerve stimulation. During the test, MEPs of all subjects showed a potentiation; this effect was markedly greater in subjects with a small initial MEP. After the test, the differential degrees of contraction-evoked potentiation still influenced the MEP amplitudes; small pre-test MEPs showed a post-test net potentiation and larger pre-test MEPs showed a net post-test depression. The results underline that the net outcome of motor activation on motor cortex excitability, as studied with TMS, depends on a complex balance of fatiguing and potentiating effects.
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Introduction: Weak direct current stimulation (tDCS) of the human motor cortex results in excitability shifts which occur during and after stimulation. These are polarity-specific with anodal tDCS enhancing excitability, and cathodal reducing it. To explore the origin of this excitability modulation, we measured the input/output curve and motor thresholds as global parameters of cortico-spinal excitability, and determined intracortical inhibition and facilitation, as well as facilitatory indirect wave (I-wave) interaction. Measurements were performed during short-term tDCS, which elicits no after-effects, and for tDCS-protocols eliciting short- and long-lasting after-effects. Methods: Twelve to twenty healthy human subjects participated in each experiment. Active and resting motor threshold, input/output curve, short-term interval inhibition/facilitation and I-wave interaction were measured by transcranial magnetic stimulation (TMS) standard paradigms. Motor cortex excitability was evaluated during short-lasting tDCS, which elicits no after-effects (4s anodal or cathodal stimulation), and for short-lasting (7min tDCS) and long-lasting (9min cathodal, 13min anodal tDCS) after-effects. Results: Resting and active motor thresholds remained stable during and after tDCS. The slope of the input/output curve was increased by anodal and decreased by cathodal tDCS. Anodal tDCS of the primary motor cortex reduced intracortical inhibition and enhanced facilitation after, but not during tDCS, while cathodal tDCS reduced facilitation during and additionally increased inhibition after its administration. During tDCS, I-wave (indirect wave) facilitation was not influenced, but for the after-effects anodal tDCS increased I-wave facilitation, while cathodal tDCS had only minor effects. Discussion: These results suggest that the effect of tDCS on cortico-spinal excitability during a short stimulation, which does not induce after-effects, primarily depends on subthreshold resting membrane potential changes, which modulate the input-output curve, but not motor thresholds. In contrast, the after-effects of tDCS are due to shifts in intracortical inhibition and facilitation, and at least partly also to facilitatory I-wave interaction, which are controlled by synaptic activity.
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Fatigue of voluntary muscular effort is a complex and multifaceted phenomenon. Fatigue of peripheral nervous system components, including the contractile apparatus and the neuromuscular junction, has been well studied. Central nervous system components also fatigue, but studies have lagged for want of objective methods. Transcranial magnetic stimulation is a relatively new technique that can be used to assess central nervous system excitability from the motor cortex to the alpha-motoneuron. In six normal volunteers, including four of the investigators, the amplitudes of motor evoked potentials elicited by transcranial magnetic stimulation were transiently decreased after exercise, indicating fatigue of motor pathways in the central nervous system. The decrease in amplitude was associated with a feeling of fatigue. The mechanism of this phenomenon is apparently decreased efficiency in the generation of the motor command in the motor cortex.
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Different aspects of attention, e.g. phasic alertness, vigilance, divided attention, response flexibility, response inhibition and intermodal integration, were investigated with a computerized test-battery in a group of 20 patients with Huntington's disease and 27 healthy controls. Huntington's disease patients are not impaired in reacting to task-contingent external stimulation in the phasic alertness task, but the self-generated maintenance of attention as measured by the vigilance task, is disturbed. The simultaneous monitoring of different input-channels in the divided attention task and the ability to operate with information given to different modalities in the intermodal integration task are severely affected. The performance of Huntington's disease patients in the response flexibility task, in which internal cued shifts are required, is impaired. Huntington's disease patients are also impaired in reacting selectively to go/no-go stimuli in the response inhibition task. It is suggested that a number of 'higher' cognitive deficits described in Huntington's disease might, at least partly, be due to basic attentional disturbances
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Introduction: Dopaminergic mechanisms participate in NMDA receptor-dependent neuroplasticity, as animal experiments have shown. This may be similar in humans, where dopamine influences learning and memory. We tested the role of dopamine in human cortical neuroplasticity. Therefore, transcranial direct current stimulation (tDCS) of the primary motor cortex was used to induce NMDA receptor-dependent excitability modulations. Methods: According to standard protocols, 9min cathodal or 13min anodal tDCS, which are known to induce motor cortical excitability reductions or enhancements outlasting the stimulation for about one hour, were administered to 4–12 healthy humans in each experiment. tDCS-elicited excitability changes were monitored by single pulse transcranial magnetic stimulation (TMS) before and up to the day after tDCS. The dopaminergic influence on neuroplasticity was tested via application of 400mg sulpiride, a D2/D3 receptor antagonist, 0.025mg pergolide, a combined D1/D2 receptor agonist, or a combination of both drugs, which results in a selective D1 receptor activation. All experiments were conducted in a placebo medication-controlled, repeated measures design. Results: D2 receptor block by sulpiride abolished the induction of after-effects nearly completely. D1 activation alone in the presence of D2 receptor block induced by co-administration of sulpiride and pergolide did not re-establish the excitability changes induced by tDCS. Enhancement of D2 Ð and to a lesser degree Ð of D1 receptors by pergolide consolidated tDCS-generated excitability diminution until the morning after stimulation. Conclusions: The readiest explanation for this pattern of results is that D2 receptor activation has a consolidation-enhancing effect on tDCS-induced changes of excitability in the human cortex. The results of this study underscore the importance of the dopaminergic system for human neuroplasticity, suggest a first pharmacological add-on mechanism to prolong the excitability-diminishing effects of cathodal tDCS for up to 24h after stimulation, and thus render the application of tDCS practicable in diseases displaying enhanced cortical excitability, e.g. migraine and epilepsy.
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Changes in motor evoked potential (MEP) amplitude, post-MEP silent period duration, and interpolated twitch torque were measured using transcranial magnetic (TMS) and electrical (TES) stimulation during a 20% maximum voluntary contraction of the elbow flexors sustained to exhaustion. TMS- and TES-induced MEP amplitude increased progressively over the contraction period up until the point of exhaustion. The TMS-induced silent period was prolonged only during the second half of the contraction period, the time course being different from that of the MEP responses, whereas the TES-induced silent period did not change. The findings indicate that corticomotor excitability increases during a sustained submaximal voluntary contraction and that, as fatigue develops, there is a progressive buildup of intracortical inhibition. This may represent a mechanism whereby corticomotor output is maintained at an appropriate level to preserve optimal motor unit firing frequencies during a fatiguing contraction. © 1997 John Wiley & Sons, Inc. Muscle Nerve 20:1158–1166, 1997
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Parkinson's disease (PD) is most often considered a disorder of movement. Whereas bradykinesia, rigidity, tremor, and postural instability result in disability, nonmotor complications in PD may be of equal or greater significance in some patients. This review will discuss many of the nonmotor complications in PD, including cognitive, autonomic, sleep, and sensory difficulties that may occur. © 2005 Movement Disorder Society
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Movement is preceded, accompanied and followed by reactions which give to the primary action its correct execution and ensure that the body's axis, together with the limbs, maintains the right balance. If these reactions are interfered with, incoordination of movement, lack of balance, hypertonia or dystonia may all appear. In the case of dystonia, postural mechanisms tend to become dominant and take over from the kinetic component of movement. In the upper limbs, the dystonic posture follows patterns analogous to those used by monkeys for postural purposes. Thus, while the initial mechanisms of movement represent highly sophisticated processes thoroughly adapted to living in an upright state, the reactions that go with the movement are more primitive and probably have a less helpful role.