European Journal of Neuroscience, Vol. 41, pp. 845–855, 2015

doi:10.1111/ejn.12840

COGNITIVE NEUROSCIENCE

Parietal transcranial direct current stimulation modulates primary motor cortex excitability s Molero-Chamizo,1,3 Walter Paulus,1 Guadalupe Nathzidy Rivera-Urbina,1,2 Giorgi Batsikadze,1 Andre Min-Fang Kuo1 and Michael A. Nitsche1 €ttingen, Go €ttingen, Germany Department of Clinical Neurophysiology, Georg-August-University Go University Pablo de Olavide, Ctra. de Utrera, km. 1, Sevilla 41013, Spain 3 University of Huelva, Huelva, Spain 1 2

Keywords: motor evoked potential, plasticity, short interval intracortical inhibition/intracortical facilitation, transcranial magnetic stimulation

Abstract The posterior parietal cortex is part of the cortical network involved in motor learning and is structurally and functionally connected with the primary motor cortex (M1). Neuroplastic alterations of neuronal connectivity might be an important basis for learning processes. These have however not been explored for parieto-motor connections in humans by transcranial direct current stimulation (tDCS). Exploring tDCS effects on parieto-motor cortical connectivity might be functionally relevant, because tDCS has been shown to improve motor learning. We aimed to explore plastic alterations of parieto-motor cortical connections by tDCS in healthy humans. We measured neuroplastic changes of corticospinal excitability via motor evoked potentials (MEP) elicited by singlepulse transcranial magnetic stimulation (TMS) before and after tDCS over the left posterior parietal cortex (P3), and 3 cm posterior or lateral to P3, to explore the spatial specificity of the effects. Furthermore, short-interval intracortical inhibition/intracortical facilitation (SICI/ICF) over M1, and parieto-motor cortical connectivity were obtained before and after P3 tDCS. The results show polarity-dependent M1 excitability alterations primarily after P3 tDCS. Single-pulse TMS-elicited MEPs, M1 SICI/ICF at 5 and 7 ms and 10 and 15 ms interstimulus intervals (ISIs), and parieto-motor connectivity at 10 and 15 ms ISIs were all enhanced by anodal stimulation. Single pulse-TMS-elicited MEPs, and parieto-motor connectivity at 10 and 15 ms ISIs were reduced by cathodal tDCS. The respective corticospinal excitability alterations lasted for at least 120 min after stimulation. These results show an effect of remote stimulation of parietal areas on M1 excitability. The spatial specificity of the effects and the impact on parietal cortex– motor cortex connections suggest a relevant connectivity-driven effect.

Introduction In humans, the anterior parietal cortex is a primary area for processing sensory information, whereas posterior regions of the parietal cortex appear to be involved in the integration of sensory and motor activities (Krause et al., 2012). In particular, the posterior parietal cortex is related to motor learning (Shum et al., 2001). Performance of motor tasks enhances the activity of this area (Honda et al., 1998). Specifically, connections between the parietal, primary motor and premotor cortices are thought to convey information relevant for planning of movements in space. Connections between the parietal and motor cortices are functionally enhanced during early stages of planning of reaching movements (Koch et al., 2008a,b). Alterations of cellular activity during learning, especially in the form of long-term potentiation (Rioult-Pedotti et al., 1998, 2000;

Correspondence: Guadalupe Nathzidy Rivera-Urbina, 2University Pablo de Olavide, as above. E-mail: [email protected] The experiments were conducted at the University Medical Center, Deptartment of Clinical Neurophysiology, Georg-August-University, G€ottingen. Received 26 October 2014, revised 19 December 2014, accepted 22 December 2014

Malenka & Bear, 2004; Ziemann et al., 2008), have been observed for topographically distant, but functionally interconnected, areas (Chen et al., 2003; Koch et al., 2008a,b). In motor learning, interregional connectivity involves a distributed cortical network including the primary motor cortex (M1), supplementary motor area, premotor and parietal cortices (Vahdat et al., 2011). Direct physiological effects of acute parietal cortex activation on M1 excitability and activity have been reported (Koch et al., 2007, 2008a,b). Specifically, facilitatory connections between the caudal part of the inferior parietal sulcus and the ipsilateral motor cortex have been identified by transcranial magnetic stimulation (TMS) (Koch et al., 2007; Karabanov et al., 2013). Moreover, using cortico-cortical paired associative stimulation, Koch et al. (2013) and Veniero et al. (2013) have recently demonstrated bidirectional plasticity of parietal cortex–motor cortex connectivity. Plastic changes of these interregional connections induced by transcranial direct current stimulation (tDCS) applied over the posterior parietal cortex have not been systematically explored. This might however be important for applications as tDCS has been shown to improve motor learning in humans (Nitsche et al., 2003c; Antal et al., 2004), and parietal stimulation might offer a new approach for improving respective processes.

© 2015 Federation of European Neuroscience Societies and John Wiley & Sons Ltd

846 G. N. Rivera-Urbina et al. Here we explore the impact of plasticity induction of the parietal cortex by tDCS on excitability of the ipsilateral M1 in healthy humans, in order to learn more about plasticity of these functionally interconnected areas. tDCS is a non-invasive brain stimulation tool which enables the induction of plasticity via application of weak direct currents through the scalp (Nitsche & Paulus, 2000; Nitsche et al., 2002; Priori et al., 2009). The primary effect is a polaritydependent shift in resting membrane potentials, and sufficiently long stimulation results in long-lasting excitability enhancements or reductions which depend on the glutamatergic and GABAergic systems (Nitsche & Paulus, 2001, 2011; Nitsche et al., 2003a,b, 2005; Stagg et al., 2009). tDCS is suited to the exploration of plasticity of interregional cortical connectivity, as shown by its ability to induce plasticity of premotor–motor cortex connections (Boros et al., 2008), and has been shown to improve motor learning (Nitsche et al., 2003c; Reis et al., 2009). We hypothesized that excitabilityenhancing anodal tDCS applied to the posterior parietal cortex (P3) will enhance M1 excitability, while cathodal tDCS over the same area will result in antagonistic effects.

Materials and methods Subjects Thirty-seven right-handed healthy subjects, 17 men and 20 women, aged 20–54 years (mean age 28.6  8.0 years), participated in this project. Fourteen of them, seven men and seven women, aged 20– 48 years (mean age 28.3  9.4 years), participated in experiment 1a. Thirteen subjects, seven men and six women, aged 24–54 years (mean age 28.6  8.0 years), participated in experiment 1b (two of them had also participated in the previous one). In the last two experiments (2a and b), 15 subjects (three of whom had taken part in the second experiment), five men and 10 women, aged 19– 31 years (mean age 25.7  3.4 years) were included. None of the participants was taking medication, and none reported previous or present neurological or psychiatric diseases. All subjects gave informed written consent before participation and were compensated for participation. The study was approved by the Ethics Committee of the University of G€ottingen, and conforms to the World Medical Association Declaration of Helsinki. Plasticity induction by tDCS tDCS was performed by battery-driven constant-current stimulators (NeuroConn GmbH, Ilmenau, Germany and Starstim Neuroelectrics, Barcelona, Spain) with conductive rubber electrodes, placed between two saline-soaked sponges. The electrode size used for parietal tDCS was 15 cm² (3 9 5 cm). The return electrode size was 35 cm² (7 9 5 cm). Taking into account the smaller size of the parietal target electrode, as compared to the usual motor cortex stimulation electrode size, we adjusted current intensity to result in similar current densities under the electrodes (Nitsche & Paulus, 2001). The return electrode was placed over the right supraorbital ridge. To stimulate the left parietal cortex, the respective electrode was placed over the P3 position according to the 10–20 EEG international system (Herwig et al., 2003), as well as 3 cm lateral or posterior to P3 in single experiments. The electrodes were held onto the head by elastic rubber bands. Direct current stimulation was performed for 15 min at 0.5 mA, with gradual increase and decrease for 8 s at the beginning and the end of stimulation, respectively. Similar stimulation protocols result in excitability changes stable for ~1 h after motor cortex tDCS

(Nitsche & Paulus, 2001). All subjects felt a mild tingling sensation under the active and return electrodes, which subsided during the first minutes. Subjects were blind to tDCS conditions. Each subject received direct current stimulation of the left parietal cortex (P3), both anodal and cathodal, in randomized order and on separate days at least 1 week apart. For sham tDCS, current was increased and then decreased over 8 s at both the beginning and the end of a 15min tDCS session in order to ensure perception of some tingling sensation under the electrodes, but the participants did not receive stimulation during the remainder of the session. Monitoring of motor cortex excitability by TMS TMS was accomplished by a standard double (figure-of-eight shaped) 70-mm coil connected to a Magstim 200 magnetic stimulator (Magstim, Whiteland, Dyfed, UK) for obtaining single-pulse TMS-elicited motor evoked potentials (MEPs). The coil was placed tangentially to the scalp, with the handle pointing posterolaterally at a 45° angle from the midline. The optimal position was considered as the site where TMS resulted consistently in the largest MEP in the resting target muscle, the right first dorsal interosseus muscle (FDI). The representation of the M1 was marked on the scalp with a skin marker. Surface electromyography was recorded from the right FDI by use of Ag–AgCl electrodes. The active electrode was placed over the FDI belly, and the reference electrode over the tendon of the FDI. The signals were amplified and filtered (2 Hz to 2 kHz, sampling rate 5 kHz), digitized with a micro 1401 AD converter (Cambridge Electronic Design, Cambridge, UK), and recorded by computer software (SIGNAL, Cambridge Electronic Design, version 2.13) for off-line analysis. Resting motor threshold (RMT) was defined as the lowest stimulus intensity that elicited a peak-to-peak MEP amplitude of 50 lV or more in the resting muscle in at least three out of six recordings. Active motor threshold (AMT) was obtained during moderate tonic contraction (~15% of the maximum muscle strength), and was considered to be the minimum intensity eliciting an MEP of superior size in relation to moderate spontaneous muscular background activity in at least three out of six trials (Nitsche et al., 2005). For obtaining single test pulse MEPs, the TMS intensity which resulted in an average MEP amplitude of ~1 mV peak-to-peak before tDCS was identified for baseline determination, and kept constant throughout the rest of the experiment unless adjusted in the case of double stimulation protocols. Short-interval intracortical inhibition and intracortical facilitation (SICI/ICF) within the M1 were obtained by a paired-pulse TMS protocol. The intensity of the conditioning stimulus (CS) was set to 70% of the AMT, and the test stimulus (TS) was adjusted to the intensity to evoke an MEP of ~1 mV peak-to-peak amplitude. Interstimulus intervals (ISIs) between the pairs of stimuli were 2, 3, 5, 7, 10 and 15 ms. We pooled data for inhibitory ISIs (2 and 3 ms), neutral ISIs (5 and 7 ms) and facilitatory ISIs (10 and 15 ms). The exact intervals between successive pairs of stimuli were randomized (4  0.4 s). The pairs of stimuli were organized in randomized and mixed order in 13 blocks, in which each ISI was represented once and an additional single test pulse was applied. The mean peak-topeak amplitude of the conditioned MEP at each ISI was expressed as a percentage of the mean peak-to peak size of the response to the unconditioned TS. In the paired-pulse twin-coil TMS protocol, which was conducted to explore parieto-motor connectivity, the test pulse was applied via a 50-mm figure-of-eight-shaped coil placed over the M1 representation of the right FDI. The conditioning stimulus was applied by a

© 2015 Federation of European Neuroscience Societies and John Wiley & Sons Ltd European Journal of Neuroscience, 41, 845–855

848 G. N. Rivera-Urbina et al. A

Baseline TMS

tDCS

Monitoring motor cortex excitability

Experiment 1a 20 MEPs

MEPs immediatly after tDCS, then 30 and 60 minutes after stimulation

Anodal, cathodal or sham P3 tDCS 0

Experiment 1b 20 MEPs

Anodal, cathodal or sham P3 tDCS. Anodal or cathodal tDCS 3 cm lateral or posterior to P3

B

Baseline TMS

Anodal, cathodal or sham P3 tDCS

60

90

120

SICI/ICF

0

tDCS

60

MEPs every 5 min for 30 min, then every 30 min until 2 hours

0 5 10 15 20 25 30

Experiment 2a SICI/ICF

30

Monitoring motor cortex excitability

Experiment 2b P3- M1 connectivity, twin coil TMS

P3- M1 connectivity, twin coil TMS

Anodal, cathodal or sham P3 tDCS

0

Fig. 1. Course of the experiments. (A) MEPs elicited by single-pulse TMS over the motor cortex representation of the right FDI were recorded at 1-mV intensity (baseline), then tDCS (anodal, cathodal or sham) was administered over P3 (experiments 1a and 1b) and 3 cm lateral and 3 cm posterior to P3 (experiment 1b). Immediately after the stimulation, 20 MEPs were recorded, then 30 and 60 min later (experiment 1a), and every 5 min for 30 min, then every 30 min until 2 h (experiment 1b). SICI/ICF elicited by double-pulse TMS over the motor cortex representation of the FDI were recorded with a CS of 70% of the AMT and a TS at 1 mV MEP amplitude size. Then, anodal, cathodal or sham P3 tDCS was applied and SICI/ICF were recorded again (experiment 2a). (B) Finally, a twin-coil TMS protocol was used to study P3–M1 cortico-spinal connectivity. TMS was applied over the motor cortex representation of the FDI at an intensity resulting in MEP amplitudes of ~1 mV, and CS was applied over P3 at 90% of RMT. Then, anodal, cathodal or sham P3 tDCS were applied and parieto-motor cortical were again recorded (experiment 2b).

In all experiments the Mauchley test for proving sphericity was applied. The Greenhouse–Geisser correction was applied to correct for non-sphericity, if necessary. Baseline differences between anodal, cathodal and sham tDCS were explored for non-standardized MEP amplitudes via a one-factorial ANOVA with the factor tDCS condition. A repeated-measures ANOVA with the dependent variable percentage of maximal stimulator output was conducted for motor thresholds. The critical level of significance was set to P < 0.05 for all tests. Post hoc tests were not corrected for multiple comparisons. All analyses were carried out using SPSS software. In experiment 1a, for the respective repeated-measures ANOVA, baseline-standardized MEP amplitudes from each subject served as the dependent variable, and tDCS condition (anodal/cathodal) and time as within-subject factors. In the case of significant results, post hoc two-tailed paired-samples Student0 s t-tests were conducted to compare MEP amplitude alterations of the respective time bins vs. baseline, or within a time bin between tDCS conditions. A one-way ANOVA, with time as a repeated-measures factor and MEP as dependent variable, was conducted for sham stimulation in a subgroup of subjects. For the repeated-measures ANOVA of experiment 1b, baseline-standardized MEP amplitudes from each subject served as the dependent variable, and tDCS condition (anodal/cathodal/sham), time and electrode position served as within-subject factors. In the case of significant results of the ANOVA, post hoc two-tailed paired-samples Student0 s t-tests were conducted to compare MEP amplitude

alterations of the respective time bins vs. baseline, or within a time bin between tDCS conditions. Two separate ANOVAS were conducted for experiments 2a and 2b. For the respective repeated-measures ANOVAS, single TMS test pulsestandardized double-pulse TMS-elicited MEP amplitudes from each subject served as the dependent variable, and tDCS condition (anodal/cathodal/sham), time (before and after tDCS) and ISIs (pooled data for 2 and 4 ms, 6 and 8 ms and 10 and 15 ms ISIs) served as repeated-measures factors. When the results were significant, post hoc two-tailed paired-samples Student0 s t-tests were conducted to compare MEP amplitude alterations of the respective ISIs vs. baseline or sham, or within an ISI between tDCS conditions.

Results None of the subjects reported any relevant adverse effects during or after the study in any of the experiments. Baseline values of MEPs, RMT, AMT, SICI/ICF and parieto-motor cortical connectivity did not differ between sessions in the respective experiments before tDCS (Table 1). Experiment 1a The repeated-measures ANOVA conducted for single test-pulse MEP (Table 2) showed a significant main effect of polarity (P = 0.002) and a significant effect of the interaction between time and

© 2015 Federation of European Neuroscience Societies and John Wiley & Sons Ltd European Journal of Neuroscience, 41, 845–855

848 G. N. Rivera-Urbina et al. A

Baseline TMS

tDCS

Monitoring motor cortex excitability

Experiment 1a 20 MEPs

MEPs immediatly after tDCS, then 30 and 60 minutes after stimulation

Anodal, cathodal or sham P3 tDCS 0

Experiment 1b 20 MEPs

Anodal, cathodal or sham P3 tDCS. Anodal or cathodal tDCS 3 cm lateral or posterior to P3

B

Baseline TMS

Anodal, cathodal or sham P3 tDCS

60

90

120

SICI/ICF

0

tDCS

60

MEPs every 5 min for 30 min, then every 30 min until 2 hours

0 5 10 15 20 25 30

Experiment 2a SICI/ICF

30

Monitoring motor cortex excitability

Experiment 2b P3- M1 connectivity, twin coil TMS

P3- M1 connectivity, twin coil TMS

Anodal, cathodal or sham P3 tDCS

0

Fig. 1. Course of the experiments. (A) MEPs elicited by single-pulse TMS over the motor cortex representation of the right FDI were recorded at 1-mV intensity (baseline), then tDCS (anodal, cathodal or sham) was administered over P3 (experiments 1a and 1b) and 3 cm lateral and 3 cm posterior to P3 (experiment 1b). Immediately after the stimulation, 20 MEPs were recorded, then 30 and 60 min later (experiment 1a), and every 5 min for 30 min, then every 30 min until 2 h (experiment 1b). SICI/ICF elicited by double-pulse TMS over the motor cortex representation of the FDI were recorded with a CS of 70% of the AMT and a TS at 1 mV MEP amplitude size. Then, anodal, cathodal or sham P3 tDCS was applied and SICI/ICF were recorded again (experiment 2a). (B) Finally, a twin-coil TMS protocol was used to study P3–M1 cortico-spinal connectivity. TMS was applied over the motor cortex representation of the FDI at an intensity resulting in MEP amplitudes of ~1 mV, and CS was applied over P3 at 90% of RMT. Then, anodal, cathodal or sham P3 tDCS were applied and parieto-motor cortical were again recorded (experiment 2b).

In all experiments the Mauchley test for proving sphericity was applied. The Greenhouse–Geisser correction was applied to correct for non-sphericity, if necessary. Baseline differences between anodal, cathodal and sham tDCS were explored for non-standardized MEP amplitudes via a one-factorial ANOVA with the factor tDCS condition. A repeated-measures ANOVA with the dependent variable percentage of maximal stimulator output was conducted for motor thresholds. The critical level of significance was set to P < 0.05 for all tests. Post hoc tests were not corrected for multiple comparisons. All analyses were carried out using SPSS software. In experiment 1a, for the respective repeated-measures ANOVA, baseline-standardized MEP amplitudes from each subject served as the dependent variable, and tDCS condition (anodal/cathodal) and time as within-subject factors. In the case of significant results, post hoc two-tailed paired-samples Student0 s t-tests were conducted to compare MEP amplitude alterations of the respective time bins vs. baseline, or within a time bin between tDCS conditions. A one-way ANOVA, with time as a repeated-measures factor and MEP as dependent variable, was conducted for sham stimulation in a subgroup of subjects. For the repeated-measures ANOVA of experiment 1b, baseline-standardized MEP amplitudes from each subject served as the dependent variable, and tDCS condition (anodal/cathodal/sham), time and electrode position served as within-subject factors. In the case of significant results of the ANOVA, post hoc two-tailed paired-samples Student0 s t-tests were conducted to compare MEP amplitude

alterations of the respective time bins vs. baseline, or within a time bin between tDCS conditions. Two separate ANOVAS were conducted for experiments 2a and 2b. For the respective repeated-measures ANOVAS, single TMS test pulsestandardized double-pulse TMS-elicited MEP amplitudes from each subject served as the dependent variable, and tDCS condition (anodal/cathodal/sham), time (before and after tDCS) and ISIs (pooled data for 2 and 4 ms, 6 and 8 ms and 10 and 15 ms ISIs) served as repeated-measures factors. When the results were significant, post hoc two-tailed paired-samples Student0 s t-tests were conducted to compare MEP amplitude alterations of the respective ISIs vs. baseline or sham, or within an ISI between tDCS conditions.

Results None of the subjects reported any relevant adverse effects during or after the study in any of the experiments. Baseline values of MEPs, RMT, AMT, SICI/ICF and parieto-motor cortical connectivity did not differ between sessions in the respective experiments before tDCS (Table 1). Experiment 1a The repeated-measures ANOVA conducted for single test-pulse MEP (Table 2) showed a significant main effect of polarity (P = 0.002) and a significant effect of the interaction between time and

© 2015 Federation of European Neuroscience Societies and John Wiley & Sons Ltd European Journal of Neuroscience, 41, 845–855

Effects of tDCS over P3 on M1 excitability 849 Table 1. MEP amplitudes for baselines and motor thresholds Experimental session

SI 1 mV (% MSO)

Baseline MEP amplitude (mV)

Experiment 1a Anodal tDCS over P3 Cathodal tDCS over P3 Sham tDCS over P3

45.7  6.2 46  6.5 47.1  3.7

1.03  0.09 1.06  0.07 1.09  0.07

Experiment 1b Anodal tDCS over P3 Cathodal tDCS over P3 Sham tDCS over P3 Anodal tDCS over 3 cm post toP3 Cathodal tDCS over 3 cm post toP3 Anodal tDCS over 3 cm lat toP3 Cathodal tDCS over 3 cm lat toP3

50.2 47.9 50.0 51.3 49.8 49.3 49.6

Experiment 2a Before stimulation Anodal tDCS over P3 Cathodal tDCS over P3 Sham tDCS over P3 After stimulation Anodal tDCS over P3 Cathodal tDCS over P3 Sham tDCS over P3 Experiment 2b Before stimulation Anodal tDCS over P3 Cathodal tDCS over P3 Sham tDCS over P3 After stimulation Anodal tDCS over P3 Cathodal tDCS over P3 Sham tDCS over P3

      

9.9 10.2 10.7 11.3 10.5 10.2 10.1

1.05 1.03 1.06 1.02 1.02 1.01 0.99

      

AMT (% MSO)

RMT (% MSO)

0.02 0.06 0.10 0.07 0.10 0.06 0.07

42.0  5.6 41.3  5.5 42.6  5.4

1.18  0.15 1.16  0.13 1.12  0.17

29.6  4.2 30.3  2.9 29.6  4.7

41.4  6.5 40.8  5.6 42.2  5.7

1.12  0.16 1.12  0.18 1.14  0.14

29.8  3.8 29.6  4.0 29.8  4.2

65.8  7.1 66.0  7.7 66.6  6.5

1.12  0.17 1.03  0.13 1.04  0.15

35.1  4.2 *35.6  4.5 35.6  4.0

65.2  6.9 66.9  7.1 67.0  7.2

1.03  0.13 1.06  0.13 1.10  0.12

34.13  4.4 *36.6  5.0 35.6  3.7

Data are presented as mean  SD; TMS, transcranial magnetic stimulation; SI 1mv, TMS intensity adjusted to elicit ~1 mV peak-to-peak amplitude of motor evoked potentials (MEPs). RMT, resting motor threshold; AMT, active motor threshold; % MSO, percentage of maximum stimulator output. *P < 0.05 for RMT before vs. after stimulation.

polarity (P = 0.002). The post hoc tests show significant MEP enhancements vs. baseline in the anodal condition immediately after tDCS and 60 min after stimulation (P ˂ 0.05). In the cathodal tDCS condition, MEP size was significantly reduced vs. baseline only immediately after tDCS (P ˂ 0.05). The comparison between anodal and cathodal tDCS showed significant differences immediately after tDCS, 30 and 60 min after stimulation (P < 0.05). The one-way ANOVA conducted for sham tDCS showed no significant effect of time (P = 0.431). Figure 2 shows the MEP alterations induced by anodal, cathodal and sham parietal tDCS. Experiment 1b The repeated-measures ANOVA conducted for single test-pulse MEP showed a significant main effect of stimulation (P = 0.006) and time (P = 0.040), and a significant interaction between electrode position and tDCS (P ≤ 0.001), electrode position and time (P = 0.006), and electrode position, tDCS and time (P = 0.007) (Table 2). Post hoc tests revealed MEP enhancements in the anodal condition vs. baseline immediately after P3 tDCS (0 min), as well as 5, 15, 20, 30, 60, 90 and 120 min after stimulation (P < 0.05). In the cathodal P3 tDCS condition, MEP size was significantly reduced vs. baseline at 5, 10, 15, 20, 25, 30, 60, 90 and 120 min after stimulation (P < 0.05). The post hoc tests showed a significant MEP increase in the anodal P3 tDCS condition

compared with sham at 30, 60, 90 and 120 min after tDCS (P < 0.05). Regarding the cathodal P3 tDCS condition, compared with sham there was a significant MEP decrease at 5, 10, 15, 20, 25, 30, 60 and 120 min after tDCS (P < 0.05). Figure 3A shows the motor cortex excitability changes after anodal, cathodal and sham P3 tDCS. Post hoc tests for the position 3 cm posterior to P3 (Fig. 3B) showed MEP enhancements in the anodal condition compared to baseline at 90 and 120 min (P < 0.05), and sham at 10 min (P < 0.05). MEP decreases were observed in the cathodal condition compared to baseline at 10, 60, 90 and 120 min (P < 0.05), and sham at 10 and 60 min (P < 0.05). The post hoc tests results for the position 3 cm lateral to P3 indicated no significant MEP changes in anodal or cathodal tDCS conditions. In the sham condition, no MEP changes were found. The results obtained with these tDCS positions are shown in Fig. 3C. Experiment 2a Motor thresholds did not differ between experimental sessions before and after tDCS (Table 1). The repeated-measures ANOVA (Table 2) shows a significant main effect of ISI (P ˂ 0.001) and a significant tDCS condition and time interaction (P = 0.007). The results of the post hoc tests revealed significant MEP enhancements in the anodal condition vs. baseline and sham stimulation for the ISIs 5 and 7 ms and 10 and 15 ms (P < 0.05). Figure 4A shows the SICI/ICF results in the anodal condition. Post hoc tests for

© 2015 Federation of European Neuroscience Societies and John Wiley & Sons Ltd European Journal of Neuroscience, 41, 845–855

850 G. N. Rivera-Urbina et al. ANOVAs

Experiment 1a tDCS polarity TMS time Time 9 polarity Single test pulse TMS time (sham) Experiments 1b tDCS position tDCS stimulation TMS time tDCS position 9 tDCS stimulation tDCS position 9 TMS time tDCS stimulation 9 TMS time tDCS position 9 tDCS stimulation 9 TMS time Experiment 2a tDCS stimulation TMS time ISIs tDCS stimulation 9 TMS time tDCS stimulation 9 ISIs Time 9 ISIs Stimulation 9 TMS time 9 ISIs Experiment 2b tDCS stimulation TMS time ISIs tDCS stimulation 9 TMS time tDCS stimulation 9 ISIs TMS time 9 ISIs Stimulation 9 TMS time 9 ISIs

1 3 3 3 2 2 10 4 20 20 40

F-value

14.3 1.3 5.9 0.7 1.695 5.019 1.928 7.822 1.814 0.967 1.698

P-value

0.002* 0.281 0.002* 0.431 0.205 0.015* 0.048* ˂0.001* 0.020* 0.503 0.006*

1.6

MEP amplitude (mV)

d.f

A 1.8

*

0.187 1.839 33.710 5.929 .959 1.773 0.042

0.830 0.197 ˂0.001* 0.007* 0.437 0.188 0.213

2 1 2 2

2.994 0.613 0.457 3.988

0.69 0.447 0.638 0.030*

2 4

0.220 2.364

0.804 0.064

*

1.2 1 0.8 0.6 0.4

Anodal

0.2

Cathodal

0 0

30

60

Time course (min)

B 2 1 2 2 4 2 4

*

1.4

1.8 1.6

MEP amplitude (mV)

Table 2. Results of the

1.4 1.2 1.0 0.8 0.6 0.4

Sham

0.2 0.0 0

Two-way repeated-measures ANOVAs were calculated for single test-pulse transcranial magnetic stimulation (TMS), and one-way repeated-measures ANOVA was conducted for single pulse MEPs in the sham condition (experiment 1a). Three-way repeated-measure ANOVAs were calculated for MEPs, short intracortical inhibition and intracortical facilitation (SICI/ICF), and twin coil TMS (experiments 1b, 1c, 2a and 2b). *P < 0.05. d.f., degrees of freedom.

cathodal tDCS indicated no significant differences vs. baseline or sham (Fig. 4B). In the sham condition, no MEP changes were found (Fig. 4C).

30

60

Time course (min) Fig. 2. MEP amplitudes for (A) anodal and cathodal tDCS and (B) sham stimulation over P3 (experiment 1a). (A) Compared to baseline values, MEP amplitudes were significantly larger in the anodal condition 0 min and 60 min (♦P < 0.05) after posterior parietal tDCS (P3), and significantly diminished in the cathodal condition 0 min after P3 tDCS (■P < 0.05). MEPs were significantly larger after anodal than cathodal P3 tDCS, immediately, 30 min and 60 min (*P < 0.05) after tDCS. (B) Sham tDCS did not result in any MEP alterations. The dotted line indicates baseline MEP amplitude. (♢) Anodal tDCS. (□) Cathodal tDCS. (D) Sham tDCS. (♦) Anodal tDCS vs baseline significance. (■) Cathodal tDCS vs baseline significance. *Anodal vs cathodal tDCS significance. Error bars represent SEM.

Experiment 2b Motor thresholds did not differ between experimental sessions before and after tDCS except for RMT in the cathodal stimulation condition, where threshold values were enhanced after tDCS (Table 1). No effects of the double stimulation protocol on MEP size took place before tDCS. The repeated-measures ANOVA (Table 2) shows a significant interaction between tDCS condition and time (P = 0.030). The results of the post hoc tests indicate significant MEP enhancements in the anodal condition compared to baseline and sham (P < 0.05) for the ISIs 10 and 15 ms (Fig. 5A). In the cathodal condition, MEP amplitudes decreased compared to sham (P < 0.05) for the same ISIs (Fig. 5B). In the sham condition, no MEP changes were found (Fig. 5C).

Discussion The data show that posterior parietal (P3) tDCS induces polaritydependent M1 excitability changes. P3 anodal tDCS enhances single-pulse TMS-elicited MEP in M1, M1 intracortical changes at 5 and 7 ms and 10 and 15 ms ISIs, and parieto-motor cortical connectivity at ISIs 10 and 15 ms. P3 cathodal tDCS reduces single

pulse-TMS-elicited MEP in M1, and parieto-motor cortical connectivity at ISIs 10 and 15 ms. Cortico-spinal excitability alterations remain up to 120 min after stimulation. Anodal or cathodal tDCS 3 cm posterior or lateral to P3 does not affect M1 excitability consistently. These results provide novel findings about the capacity of tDCS to induce plasticity of parieto-motor cortical connections. Experiment 1a: M1 excitability changes induced by parietal tDCS The results of this experiment suggest that parietal tDCS alters motor cortex excitability. In particular, anodal tDCS over P3 increased excitability of M1. This effect was present for 1 h after stimulation. Cathodal tDCS over P3 reduced M1 excitability, but this effect was somewhat weaker. Sham tDCS had no effect. The direction of the effect of tDCS at P3 is the same for application of tDCS over M1; however, the duration of the effects seem to be longer-lasting than those of roughly similar anodal tDCS over the M1, whereas the after-effects of cathodal stimulation recorded over a period of 60 min are considerably shorter when compared with

© 2015 Federation of European Neuroscience Societies and John Wiley & Sons Ltd European Journal of Neuroscience, 41, 845–855

Effects of tDCS over P3 on M1 excitability 851 Anodal

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Fig. 3. MEP amplitudes for anodal, cathodal and sham tDCS (A) over the posterior parietal cortex (P3), (B) 3 cm posterior to P3 and (C) 3 cm lateral to P3 (experiment 1b). (A) P3 tDCS resulted in an MEP amplitude enhancement for anodal (♦P < 0.05), and MEP decrease for cathodal (■P < 0.05) tDCS compared to baseline. (B) Compared to baseline, MEPs were significantly diminished after anodal (♦P < 0.05) and cathodal (■P < 0.05) tDCS, when tDCS was applied 3 cm posterior to P3. Also compared to sham, MEPs were significantly decreased in the anodal (*P < 0.05) and cathodal (*P < 0.05) conditions after tDCS applied 3 cm posterior to P3. (C) tDCS applied 3 cm lateral to P3 did not result in any MEPs alterations. The dotted lines indicate baseline MEP amplitude. (♢) Anodal tDCS. (□) Cathodal tDCS. (M) Sham tDCS. (♦) Anodal tDCS vs baseline significance. (■) Cathodal tDCS vs baseline significance. *Anodal or cathodal tDCS vs sham. Error bars represent SEM.

9 min (Nitsche & Paulus, 2001; Nitsche et al., 2003a) or 18 min of motor cortex stimulation (Monte-Silva et al., 2010). Thus the results deliver evidence that it is possible to induce neuroplastic changes of motor cortex excitability by applying stimulation over a connected area of parietal cortex. However, the results of this experiment on

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ISI (ms) Fig. 4. Motor cortex SICI/ICF for (A) anodal, (B) cathodal and (C) sham tDCS (experiment 2a). The CS was set to an intensity of 70% of the AMT. TS intensity was adjusted to evoke an MEP of ~1 mV peak-to-peak amplitude. TS amplitude was adjusted after tDCS when necessary. ISIs were 2, 3, 5, 7, 10 and 15 ms (arranged in the abscissa in three groups of intervals of 2 and 3 ms, 5 and 7 ms and 10 and 15 ms). (A) Significant ICF alterations were present in the anodal condition for the ISIs 5 and 7 ms and 10 and 15 ms, compared to baseline (P < 0.05) and sham (*P < 0.05). (B) Cathodal tDCS did not result in any significant change in SICI/ICF compared to baseline or sham. (C) Sham tDCS had no significant effect on SICI/ICF. (+) Before tDCS condition. (○) After tDCS condition. () After sham tDCS. () Anodal tDCS vs. baseline significance. (*) Anodal tDCS vs sham significance. Error bars represent SEM.

its own do not allow us to conclude if this is a connectivity-driven effect or one due to current spread to M1. Two different areas near to P3 were stimulated in the next experiment in order to explore the spatial specificity of the effects.

© 2015 Federation of European Neuroscience Societies and John Wiley & Sons Ltd European Journal of Neuroscience, 41, 845–855

852 G. N. Rivera-Urbina et al. Fig. 5. Parieto-motor cortical connectivity after posterior parietal cortex (P3) tDCS recorded by paired-pulse parieto-motor cortex TMS (experiment 2b). The conditioning stimulus (CS) was applied over P3 and the test stimulus (TS) was applied over the M1 representation of the right FDI. CS intensity was set to 90% RMT. TS was adjusted to the intensity to evoke ~1 mV peak-to-peak amplitude MEP of the right first dorsal interosseus muscle (FDI). Interstimulus intervals (ISIs) were 2, 4, 6, 8, 10, and 15 ms (arranged in the abscissa in three groups of intervals of 2 and 4, 6 and 8, and 10 and 15 ms). Twenty single pulse MEPs and ten conditioned MEP for each ISI were registered, and then anodal (A), cathodal (B) and sham (C) P3 tDCS was applied. Significant cortico-cortical facilitatory changes were found after anodal stimulation (A) for the ISIs 10 and 15 compared to baseline (P < 0.05) and sham (*P < 0.05). MEPs were significantly reduced after cathodal tDCS (B) for the ISIs 10 and 15 compared to sham (*P ≤ 0.05). Sham tDCS (C) did not result in any significant change of parieto-motor cortical connectivity. (+) Before tDCS condition. (○) After tDCS condition. () After sham tDCS. () Anodal tDCS vs. baseline significance. (*) Anodal or cathodal tDCS vs sham significance. Error bars represent standard error of means (SEM).

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excitability changes only 10 and 60 min after stimulation. In contrast, anodal tDCS over P3 increased M1 excitability for 120 min after stimulation. Cathodal tDCS over P3 reduced M1 excitability, and this effect recorded over a period of 120 min lasted from 5 min to 2 h after stimulation. Thus, the neuroplastic changes induced by tDCS occur grossly when the stimulation is directly applied over P3, which is compatible with a primarily cortico-cortical connectivity effect (Koch et al., 2008a,b; Karabanov et al., 2012, 2013). Interestingly, in this experiment the cathodal effects seem to be more robust than those in experiment 1a, a difference which might be due to intergroup differences in participants. Even though these findings are clear, the spatial specificity of the effects of parietal tDCS could not be resolved completely. A related study (Karabanov et al., 2013) reports high variability of coil positions to reveal parieto-motor cortical connectivity using double-pulse TMS. Moreover, TMS of different parietal areas (e.g. along the intraparietal sulcus or anterior parietal cortex) can have different effects on parieto-motor cortical connectivity (Karabanov et al., 2013). Despite this spatial variability, however, in experiment 1b neighbouring but spatially discernible electrode positions did not result in a clear effect of tDCS on M1 excitability, which suggests that with the P3 tDCS electrode position we modulated relevant parieto-motor cortical connections. The specific origin of these connections should be explored in future studies with the aid of neuronavigation, and possibly MRI-based functional and anatomical connectivity analysis. Since the primary scope of the study was not the exploration of the exact duration of the effects, but of the spatial specificity, we did stop monitoring MEP amplitudes 2 h after tDCS. The somewhat unexpectedly long after-effects of stimulation thus prevent definite assumptions about the exact duration of the tDCS-induced excitability alterations. This relevant topic should be explored in future studies.

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Experiment 1b: spatial specificity of the effects of parietal tDCS on M1 excitability tDCS of areas situated near to P3 had no consistent effect on M1 excitability. Anodal and cathodal tDCS 3 cm lateral to P3 did not cause any change in M1 excitability. Anodal and cathodal tDCS conducted 3 cm posterior to P3 induced minor, but significant,

Anodal tDCS over P3 resulted in excitatory effects for neutral (5 and 7 ms) and facilitatory (10 and 15 ms) ISIs. In contrast, cathodal tDCS over P3 did not alter M1 intracortical excitability. Therefore, anodal parietal tDCS can activate pathways of intracortical facilitation of motor cortex neurons. Another study has shown similar SICI/ICF changes after premotor cortex tDCS (Boros et al., 2008), although in this case the pattern of induced plasticity was not exactly the same. In that study, anodal tDCS of the premotor cortex

© 2015 Federation of European Neuroscience Societies and John Wiley & Sons Ltd European Journal of Neuroscience, 41, 845–855

Effects of tDCS over P3 on M1 excitability 853 enhanced the intracortical facilitation of the M1 and reduced intracortical inhibition, but had no impact on single-pulse TMS-elicited MEP amplitudes. The reason for these discernible effects is unclear at present, but they might be related to different locations of the terminations of parietal and premotor afferents on M1 neurons (Godschalk et al., 1984; Tokuno & Nambu, 2000). Alternatively, it cannot be excluded that current spread from the parietal electrode contributed to the effects. However, the pattern of the results qualitatively differs from that of motor cortex tDCS. Here anodal tDCS enhanced intracortical facilitation and diminished intracortical inhibition, while cathodal tDCS had antagonistic effects (Nitsche et al., 2005). Therefore, a relevant contribution of current spread to the M1 cannot easily explain the results. Experiment 2b: Parietal-motor cortical connectivity changes induced by parietal tDCS Anodal and cathodal P3 tDCS induced M1 excitability changes at the facilitatory ISIs (10 and 15 ms). Specifically, anodal tDCS increased parietal cortex–motor cortex connectivity and cathodal tDCS decreased it. No excitability changes were found for the remaining ISIs (2 and 4 ms and 6 and 8 ms). Previous studies using twin-coil TMS describe motor cortex excitability alterations when a conditioning stimulus is applied over the parietal cortex (Koch et al., 2007; Koch & Rothwell, 2009; Karabanov et al., 2012, 2013). For reasons which are not absolutely clear we could not replicate these results without P3 tDCS. Nevertheless, as after tDCS polarity-dependent MEP alterations occurred, which differed qualitatively from those induced by double-pulse stimulation over the M1 (Nitsche et al., 2005), it is probable that the effects can be due to parieto-motor cortical connections. Recently it was described that parieto-motor cortical connectivity measures differ with regard to current flow direction in the TMS coil (Koch et al., 2013). Future studies should explore these effects in more detail to identify the involvement of specific connections in the after-effects of parietal tDCS on motor cortex excitability. General remarks The results of the present study show that direct current stimulation targeted at the left posterior parietal cortex (P3) induces neuroplastic changes in the excitability of the ipsilateral M1, as explored by TMS. Additional to spatial specificity, it is worth noting that these effects lasted relevantly longer than those obtained with similar motor cortex tDCS protocols, which could have important functional implications. In the first experiment, anodal stimulation of the posterior parietal cortex enhanced motor cortex cortico-spinal excitability while cathodal stimulation had antagonistic effects. These results could be partially explained by a physical current spread (Faria et al., 2001; Edwards et al., 2013), although not completely explained because P3 tDCS had a specific impact on motor cortex excitability which depended on the exact position of the stimulation electrodes. Slight deviations of electrode positions resulted in clear alterations of tDCS effects, which is difficult to explain by physical current spread alone. In accordance, the results of experiments 2a and 2b are well compatible with a predominating connectivity effect, because here parietal tDCS had a specific effect on motor cortex intracortical excitability which differs from the effect of M1 tDCS on the intracortical excitability, and also a clear effect on parieto-motor cortical connectivity. In the case of intrinsic motor cortical excitability, again a current spread effect cannot be completely ruled out, although

these results are explained more easily due to a selective influence of parietal tDCS on intracortical facilitatory networks between posterior parietal cortex and M1. This hypothesis is supported by the results of experiment 2b. Using a twin-coil TMS protocol, anodal P3 tDCS induced a facilitatory effect in the motor cortex, whereas cathodal tDCS reduced parieto-motor cortical connectivity. The impact of tDCS over the parietal cortex on motor cortex excitability is consistent with the results of previous studies in humans, and animals, in which connections between the motor and posterior parietal cortices were demonstrated (Inman et al., 2012). In humans, this anatomical connection has also been explored by TMS, showing specific regions of the parietal cortex connecting to the motor cortex (Karabanov et al., 2012, 2013). An impact of parietal tDCS on parieto-motor cortical connectivity at 10 and 15 ms ISIs has not been previously described, and might imply the activation of longer polysynaptic pathways involving subcortical structures such as the thalamus or basal ganglia (Neubert et al., 2010). In principle accordance, it has been demonstrated via fMRI that motor cortex tDCS alters functional connectivity between the stimulated cortical area, and thalamic and basal ganglia nuclei (Polanıa et al., 2012). Another interesting tool for studying the anatomical basis for non-invasive brain stimulation effects is diffusion tensor imaging (DTI) (Koch et al., 2010). Combining TMS with fMRI, including functional connectivity analysis and DTI, in future studies could help to clarify the contribution of specific pathways to respective tDCS effects. As parietal and primary motor areas are functionally interconnected during motor learning (Koch et al., 2007), it is likely that the connections between these structures undergo plastic changes, as is the case for prefrontal networks (Esslinger et al., 2014). Targeting these plastic alterations would reveal an additional tool for modulating interregional plasticity to alter motor processes. Modulation of connectivity may have implications for motor learning and motor rehabilitation processes. Underscoring the probable relevance of interregional plasticity for motor performance, some TMS studies have shown connectivity changes associated with simple motor task performance (Hortobagyi et al., 2011). For parieto-motor cortical connectivity, specifically improvement of motor memory consolidation, which critically involves the posterior parietal cortex (Grafton et al., 1995, 1998; Hazeltine et al., 1997), might be a relevant target for performance-modulating effects of tDCS. Such effects have already been demonstrated for another area, the premotor cortex, where tDCS during consolidation, but not initial, learning improved performance in a sequence learning task (Nitsche et al., 2003c, 2008). Accordingly, the functional relevance of plasticity of corticocortical connectivity induced by tDCS could be tested for motor learning tasks in future research. Moreover, the current findings might also have implications for exploring parietofrontal circuits in patients with neglect (Koch et al., 2008a,b; Sparing et al., 2009), and could be valuable for establishing new rehabilitation strategies in these patients including plasticity induction with non-invasive brain stimulation (Koch et al., 2012). In this connection, the long-lasting and spatially relatively specific after-effects of tDCS on cortical excitability are a relevant and novel finding of the present study, which might be taken advantage of in future clinical applications. In conclusion, the results of the current study deliver evidence for motor cortex plasticity induced by parietal tDCS. Knowledge about plasticity of posterior parietal cortex–M1 connectivity could help to identify mechanisms of motor learning to a larger extent. The data fit well with anatomical and functional connectivity between both areas. Nevertheless, confirmation that this effect is connectivity-driven and its functional relevance need to be obtained in future studies which

© 2015 Federation of European Neuroscience Societies and John Wiley & Sons Ltd European Journal of Neuroscience, 41, 845–855

854 G. N. Rivera-Urbina et al. will allow testing of the impact of cortico-cortical plasticity effects induced by non-invasive brain stimulation on motor learning tasks. This could clarify specifically how brain plasticity changes induced by brain stimulation protocols can modulate motor performance.

Acknowledgements M.A.N. receives support from the German Ministry for Research and Education, grant 03IPT605E. G.N.R.-U. receives support from the Mexican National Council for Science and Technology, grant 214254/30943. M.A.N. is member of the advisory board of Neuroelectrics. W.P. is member of the advisory board of EBS technologies. The remaining authors declare no conflicts of interest.

Abbreviations AMT, active motor threshold; CS, conditioning stimulus; FDI, first dorsal interosseus muscle; ISI, interstimulus interval; M1, primary motor cortex; MEP, motor-evoked potential; RMT, resting motor threshold; SICI/ICF, short interval intracortical inhibition and intracortical facilitation; tDCS, transcranial direct current stimulation; TMS, transcranial magnetic stimulation; TS, test stimulus.

References Antal, A., Nitsche, M.A., Kincses, T.Z., Kruse, W., Hoffmann, K.P. & Paulus, W. (2004) Facilitation of visuo-motor learning by transcranial direct current stimulation of the motor and extrastriate visual areas in humans. Eur. J. Neurosci., 19, 2888–2892. Boros, K., Poreisz, C., M€unchau, A., Paulus, W. & Nitsche, M.A. (2008) Premotor transcranial direct current stimulation (tDCS) affects primary motor excitability in humans. Eur. J. Neurosci., 27, 1292–1300. Chen, W.H., Mima, T., Siebner, H.R., Oga, T., Hara, H., Satow, T., Begum, T., Nagamine, T. & Shibasaki, H. (2003) Low-frequency rTMS over lateral premotor cortex induces lasting changes in regional activation and functional coupling of cortical motor areas. Clin. Neurophysiol., 114, 1628–1637. Edwards, D., Cortes, M., Datta, A., Minhas, P., Wassermann, E.M. & Bikson, M. (2013) Physiological and modeling evidence for focal transcranial electrical brain stimulation in humans: a basis for high-definition tDCS. NeuroImage, 74, 266–275. Esslinger, C., Sch€uler, N., Sauer, C., Gass, D., Mier, D., Braun, U., Ochs, E., Schulze, T.G., Rietschel, M., Kirsch, P. & Meyer-Lindenberg, A. (2014) Induction and quantification of prefrontal cortical network plasticity using 5 Hz rTMS and fMRI. Hum. Brain Mapp., 35, 140–151. Faria, P., Hallett, M. & Miranda, P.C. (2001) A finite element analysis of the effect of electrode area and inter-electrode distance on the spatial distribution of the current density in tDCS. J. Neural Eng., 8, 066017. Godschalk, M., Lemon, R.N., Kuypers, H.G. & Ronday, H.K. (1984) Cortical afferents and efferents of monkey postarcuate area: an anatomical and electrophysiological study. Exp. Brain Res., 56, 410–424. Grafton, S.T., Hazeltine, E. & Ivry, R. (1995) Functional mapping of sequence learning in normal humans. J. Cognitive Neurosci., 7, 497–510. Grafton, S.T., Hazeltine, E. & Ivry, R. (1998) Abstract and effector-specific representations of motor sequences identified with PET. J. Neurosci., 18, 9420–9428. Hazeltine, E., Grafton, S.T. & Ivry, R. (1997) Attention and stimulus characteristics determine the locus of motor-sequence encoding. A PET study. Brain, 120, 123–140. Herwig, U., Satrapi, P. & Schonfeldt-Lecuona, C. (2003) Using the international 10–20 EEG system for positioning of transcranial magnetic stimulation. Brain Topogr., 16, 95–99. Honda, M., Deiber, M.P., Iba~nez, V., Pascual-Leone, A., Zhuang, P. & Hallett, M. (1998) Dynamic cortical involvement in implicit and explicit motor sequence learning. A PET study. Brain, 121, 2159–2173. Hortobagyi, T., Richardson, S.P., Lomarev, M., Shamim, E., Meunier, S., Russman, H., Dang, N. & Hallett, M. (2011) Interhemispheric plasticity in humans. Med. Sci. Sport. Exer., 43, 1188–1199. Inman, C.S., James, G.A., Hamann, S., Rajendra, J.K., Pagnoni, G. & Butler, A.J. (2012) Altered resting-state effective connectivity of fronto-parietal motor control systems on the primary motor network following stroke. NeuroImage, 59, 227–237.

Karabanov, A., Jin, S.H., Joutsen, A., Poston, B., Aizen, J. & Ellenstein, A. (2012) Timing-dependent modulation of the posterior parietal cortex-primary motor cortex pathway by sensorimotor training. J. Neurophysiol., 107, 3190–3319. Karabanov, A.N., Chi-Chao, C., Paine, R. & Hallett, M. (2013) Mapping different intra-hemispheric parietal-motor networks using twin coil TMS. Brain Stimul., 6, 384–389. Koch, G. & Rothwell, J.C. (2009) TMS investigations into the task-dependent functional interplay between human posterior parietal and motor cortex. Behav. Brain Res., 202, 147–152. Koch, G., Fernandez Del Olmo, M., Cheeran, B., Ruge, D., Schippling, S., Caltagirone, C. & Rothwell, J.C. (2007) Focal stimulation of the posterior parietal cortex increases the excitability of the ipsilateral motor cortex. J. Neurosci., 27, 6815–6822. Koch, G., Fernandez Del Olmo, M., Cheeran, B., Schippling, S., Caltagirone, C., Driver, J. & Rothwell, J.C. (2008a) Functional interplay between posterior parietal and ipsilateral motor cortex revealed by twin-coil transcranial magnetic stimulation during reach planning toward contralateral space. J. Neurosci., 28, 5944–5953. Koch, G., Oliveri, M., Cheeran, B., Ruge, D., Lo Gerfo, E., Salerno, S., Torriero, S., Marconi, B., Mori, F., Driver, J., Rothwell, J.C. & Caltagirone, C. (2008b) Hyperexcitability of parietal-motor functional connections in the intact left-hemisphere of patients with neglect. Brain, 131, 3147–3155. Koch, G., Cercignani, M., Pecchioli, C., Versace, V., Oliveri, M., Caltagirone, C., Rothwell, J. & Bozzali, M. (2010) In vivo definition of parietomotor connections involved in planning of grasping movements. NeuroImage, 51, 300–312. Koch, G., Bonnı, S., Giacobbe, V., Bucchi, G., Basile, B., Lupo, F., Versace, V., Bozzali, M. & Caltagirone, C. (2012) h-burst stimulation of the left hemisphere accelerates recovery of hemispatial neglect. Neurology, 78, 24– 30. Koch, G., Ponzo, V., Di Lorenzo, F., Caltagirone, C. & Veniero, D. (2013) Hebbian and anti-Hebbian spike-timing-dependent plasticity of human cortico-cortical connections. J. Neurosci., 33, 9725–9733. Krause, V., Bashir, S., Pollok, B., Caipa, A., Schnitzler, A. & Pascual-Leone, A. (2012) 1 Hz rTMS of the left posterior parietal cortex (PPC) modifies sensorimotor timing. Neuropsychologia, 50, 3729–3735. Malenka, R.C. & Bear, M.F. (2004) LTP and LTD: an embarrassment of riches. Neuron, 44, 5–21. Monte-Silva, K., Kuo, M.-F., Liebetanz, D., Paulus, W. & Nitsche, M.A. (2010) Shaping the optimal repetition interval for cathodal transcranial direct current stimulation (tDCS). J. Neurophysiol., 103, 1735–1740. Neubert, F.X., Mars, R.B., Buch, E.R., Olivier, E. & Rushworth, M.F. (2010) Cortical and subcortical interactions during action reprogramming and their related white matter pathways. Proc. Natl. Acad. Sci. USA, 107, 13240–13245. Nitsche, M.A. & Paulus, W. (2000) Excitability changes induced in the human motor cortex by weak transcranial direct current stimulation. J. Physiol., 527, 633–639. Nitsche, M.A. & Paulus, W. (2001) Sustained excitability elevations induced by transcranial DC motor cortex stimulation in humans. Neurology, 57, 1899–1901. Nitsche, M.A. & Paulus, W. (2011) Transcranial direct current stimulationupdate. Restor. Neurol. Neuros., 29, 463–492. Nitsche, M.A., Liebetanz, D., Tergau, F. & Paulus, W. (2002) Modulation of cortical excitability by transcranial direct current stimulation. Nervenarzt, 73, 332–335. Nitsche, M.A., Liebetanz, D., Antal, A., Lang, N., Tergau, F. & Paulus, W. (2003a) Modulation of cortical excitability by weak direct current stimulation: technical, safety and functional aspects. Suppl. Clin. Neurophys., 56, 255–276. Nitsche, M.A., Liebetanz, D., Antal, A., Lang, N., Tergau, F. & Paulus, W. (2003b) Safety criteria for transcranial direct current stimulation (tDCS) in humans. Clin. Neurophysiol., 114, 2220–2222. Nitsche, M.A., Schauenburg, A., Lang, N., Liebetanz, D., Exner, C., Paulus, W. & Tergau, F. (2003c) Facilitation of implicit motor learning by weak transcranial direct current stimulation of the primary motor cortex in the human. J. Cognitive Neurosci., 15, 619–626. Nitsche, M.A., Seeber, A., Frommann, K., Klein, C.C., Rochford, C., Nitsche, M.S., Fricke, K., Liebetanz, D., Lang, N., Antal, A., Paulus, W. & Tergau, F. (2005) Modulating parameters of excitability during and after transcranial direct current stimulation of the human motor cortex. J. Physiol., 568, 291–303. Nitsche, M.A., Cohen, L.G., Wassermann, E.M., Priori, A., Lang, N., Antal, A., Paulus, W., Hummel, F., Boggio, P.S., Fregni, F. & Pascual-Leone, A.

© 2015 Federation of European Neuroscience Societies and John Wiley & Sons Ltd European Journal of Neuroscience, 41, 845–855

Effects of tDCS over P3 on M1 excitability 855 (2008) Transcranial direct current stimulation: state of the art. Brain Stimul., 1, 206–223. Polanıa, R., Paulus, W. & Nitsche, M.A. (2012) Modulating cortico-striatal and thalamo-cortical functional connectivity with transcranial direct current stimulation. Hum. Brain Mapp., 33, 2499–2508. Priori, A., Hallett, M. & Rothwell, J.C. (2009) Repetitive transcranial magnetic stimulation or transcranial direct current stimulation? Brain Stimul., 2, 241–245. Reis, J., Schambra, H.M., Cohen, L.G., Buch, E.R., Fritsch, B., Zarahn, E., Celnik, P.A. & Krakauer, J.W. (2009) Noninvasive cortical stimulation enhances motor skill acquisition over multiple days through an effect on consolidation. Proc. Natl. Acad. Sci. USA, 106, 1590– 1595. Rioult-Pedotti, M.S., Friedman, D., Hess, G. & Donoghue, J.P. (1998) Strengthening of horizontal cortical connections following skill learning. Nat. Neurosci., 1, 230–234. Rioult-Pedotti, M.S., Friedman, D. & Donoghue, J.P. (2000) Learninginduced LTP in neocortex. Science, 290, 533–536. Shum, M., Shiller, D.M., Baum, S.R. & Gracco, V.L. (2001) Sensorimotor integration for speech motor learning involves the inferior parietal cortex. Eur. J. Neurosci., 34, 1817–1822.

Sparing, R., Thimm, M., Hesse, M.D., K€ ust, J., Karbe, H. & Fink, G.R. (2009) Bidirectional alterations of interhemispheric parietal balance by non-invasive cortical stimulation. Brain, 132, 3011–3020. Stagg, C.J., Best, J.G., Stephenson, M.C., O`Shea, J., Wylezinska, M., Morris, P.G., Matthews, P.M. & Johansen-Berg, H. (2009) Polarity-sensitive modulation of cortical neurotransmitters by transcranial stimulation. J. Neurosci., 29, 5202–5206. Tokuno, H. & Nambu, A. (2000) Organization of nonprimary motor cortical inputs on pyramidal and nonpyramidal tract neurons of primary motor cortex: an electrophysiological study in the macaque monkey. Cereb. Cortex, 10, 58–68. Vahdat, S., Darainy, M., Milner, T.E. & Ostry, D.J. (2011) Functionally specific changes in resting-state sensorimotor networks after motor learning. J. Neurosci., 31, 16907–16915. Veniero, D., Ponzo, V. & Koch, G. (2013) Paired associative stimulation enforces the communication between interconnected areas. J. Neurosci., 33, 13773–13783. Ziemann, U., Paulus, W., Nitsche, M.A., Pascual-Leone, A., Byblow, W.D., Berardelli, A., Siebner, H.R., Classen, J., Cohen, L.G. & Rothwell, J.C. (2008) Consensus: motor cortex plasticity protocols. Brain Stimul., 1, 164– 182.

© 2015 Federation of European Neuroscience Societies and John Wiley & Sons Ltd European Journal of Neuroscience, 41, 845–855

Parietal transcranial direct current stimulation modulates primary motor cortex excitability.

The posterior parietal cortex is part of the cortical network involved in motor learning and is structurally and functionally connected with the prima...
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