brain research 1618 (2015) 61–74

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Research Report

Bilateral primary motor cortex circuitry is modulated due to theta burst stimulation to left dorsal premotor cortex and bimanual training Jason L. Nevan, Michael Vesia, Amaya M. Singh, W. Richard Staines Department of Kinesiology, University of Waterloo, Waterloo, Ontario, Canada

art i cle i nfo

ab st rac t

Article history:

Motor preparatory and execution activity is enhanced after a single session of bimanual

Accepted 23 May 2015

visuomotor training (BMT). Recently, we have shown that increased primary motor cortex (M1)

Available online 29 May 2015

excitability occurs when BMT involves simultaneous activation of homologous muscles and

Keywords:

these effects are enhanced when BMT is preceded by intermittent theta burst stimulation (iTBS)

Intermittent theta burst stimulation

to the left dorsal premotor cortex (lPMd). The neural mechanisms underlying these modulations

Bimanual visuomotor training

are unclear, but may include interhemispheric interactions between homologous M1s and

Cortical excitability

connectivity with premotor regions. The purpose of this study was to investigate the possible

Primary motor cortex

intracortical and interhemispheric modulations of the extensor carpi radials (ECR) representation

Paired-pulse TMS

in M1 bilaterally due to: (1) BMT, (2) iTBS to lPMd, and (3) iTBS to lPMd followed by BMT. This study tests three related hypotheses: (1) BMT will enhance excitability within and between M1 bilaterally, (2) iTBS to lPMd will primarily enhance left M1 (lM1) excitability, and (3) the combination of these interventions will cause a greater enhancement of bilateral M1 excitability. We used single and paired-pulse transcranial magnetic stimulation (TMS) to quantify M1 circuitry bilaterally. The results demonstrate the neural mechanisms underlying the early markers of rapid functional plasticity associated with BMT and iTBS to lPMd primarily relate to modulations of long-interval inhibitory (i.e. GABAB-mediated) circuitry within and between M1s. This work provides novel insight into the underlying neural mechanisms involved in M1 excitability changes associated with BMT and iTBS to lPMd. Critically, this work may inform rehabilitation training and stimulation techniques that modulate cortical plasticity after brain injury. & 2015 Published by Elsevier B.V.

1.

Introduction

Training movements of the upper-limb modulates the excitability in several cortical areas, such as motor (Butler and Wolf, 2007; Classen et al., 1998; Jacobs and Donoghue, 1991;

Karni et al., 1998; Kleim et al., 1998; Nudo, 2006; PascualLeone et al., 1995) and premotor (PM) (Andres et al., 1999; Deiber et al., 1996; Jennings and van der Molen, 2005; Karni et al., 1998; Smith and Staines, 2006, 2010, 2012) cortices. Critically, short-term in-phase bimanual visuomotor

n Correspondence to: Department of Physical Therapy, University of British Columbia, T142A-2211 Westbrook Mall Vancouver, BC, Canada V6L 1Z3. Telephone: +1 604 827 3369 E-mail address: [email protected] (J.L. Neva).

http://dx.doi.org/10.1016/j.brainres.2015.05.028 0006-8993/& 2015 Published by Elsevier B.V.

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training (BMT) yields a greater increase in PM cortices compared to unimanual movement training (Smith and Staines, 2006, 2010, 2012) and increases primary motor cortex (M1) excitability (Neva et al., 2012, 2014a, 2014b). Further, bimanual movement performed with the upper-limbs can increase the excitability within the damaged and undamaged M1 compared to unimanual movement in certain stroke patients (Silvestrini et al., 1998; Staines et al., 2001), and bimanual arm training can improve paretic upper-limb function (Cauraugh and Kim, 2002; Cauraugh et al., 2010; Cuadrado and Arias, 2001; Luft et al., 2004; McCombe Waller and Whitall, 2008; Mudie and Matyas, 2000; Summers et al., 2007). Despite the known enhancements in upper-limb function and increases in cortical excitability, the underlying neural mechanisms of BMT-related excitability changes remain unclear. Enhanced M1 excitability due to BMT (Neva et al., 2012, 2014b; Smith and Staines, 2006, 2010, 2012) may relate to an emphasis on the motor preparatory aspect of the trained movements, with potential neural contribution from PM areas. Motor preparatory regions, like the dorsal premotor cortex (PMd), have well-known roles in movement preparation and selection of appropriate actions for movement execution (Groppa et al., 2012; Kalaska and Crammond, 1995; O’Shea et al., 2007; Thoenissen et al., 2002). Left hemisphere PMd (lPMd) may have a particularly important role in learned visuomotor associations (Geyer et al., 2000; Toni et al., 2001) and when performing tasks with one or both upper-limbs (Johansen-Berg et al., 2002; Schluter et al., 1998, 2001). The excitatory form of theta burst stimulation (intermittent theta burst stimulation (iTBS)) applied to (dominant) lPMd causes faster preparation of complex sequences performed with the right (dominant) hand and greater enhancements in overall M1 map excitability in left (dominant) M1 (lM1) when followed by BMT, compared to BMT or iTBS to lPMd alone (Neva et al., 2014b). Further, stimulation to the ipsilesional PM areas prior to rehabilitation therapy may be a viable option to enhance ipsilesional cortical excitability and motor function in individuals with stroke with more severe disability (Cunningham et al., 2014; Plow et al., 2013, 2014). Although (dominant) lPMd potentially contributes to the BMT-related modulations in M1 excitability observed previously (Neva et al., 2012, 2014b; Smith and Staines, 2012) and to downstream ipsilesional damaged M1 in stroke rehabilitation (Cunningham et al., 2014; Plow et al., 2013, 2014), the contribution of (dominant) lPMd to the intracortical and interhemispheric neural mechanisms underlying BMTrelated excitability changes in M1 remain unclear. Another potential contributor to the modulations in M1 due to in-phase BMT are the interhemispheric interactions between homologous M1 representations, due to extensive reciprocal transcallosal connections (Asanuma and Okuda, 1962; Ferbert et al., 1992; Gould et al., 1986; Matsunami and Hamada, 1984; Meyer et al., 1995; Nelson et al., 2009; Picard and Strick, 2001). Local intracortical and interhemispheric inhibition (IHI) in M1 is decreased in the homologous M1 representation when the upper-limbs are moved synchronously (inphase), but remains with asynchronous (anti-phase) movements (Byblow et al., 2012; Stinear and Byblow, 2002, 2004). These studies suggest that interhemispheric connections

between M1 representations may be a potential neural mechanism mediating cortical excitability changes due to synchronous upper-limb movements. However, it is unclear if these interhemispheric connections are modulated by altering cortical excitability in relevant cortical preparation areas (i.e. lPMd), and when followed by BMT. Despite the known anatomical connectivity between PMd and M1 (Koch et al., 2007; Picard and Strick, 2001; Rushworth et al., 2003), and the ability to modulate M1 excitability due to rTMS over PMd (Chouinard et al., 2003; Gerschlager et al., 2001; Huang et al., 2009; Neva et al., 2014b; O’Shea et al., 2007; Ortu et al., 2009; Rizzo et al., 2004; Suppa et al., 2008), little is known about the functional significance of PMd to M1 connectivity in both hemispheres due to BMT and how bilateral M1 circuitry may be modulated by iTBS to lPMd and the combination of iTBS to lPMd followed by BMT. The purpose of the current study is to investigate the potential neural facilitatory and inhibitory circuitry contributing to the M1 excitability changes due to BMT and iTBS to lPMd observed in previous work (Neva et al., 2012, 2014b). As such, this study investigates the intracortical and interhemispheric circuitry modulations within and between M1 extensor carpi radials (ECR) representations bilaterally due to (1) BMT, (2) iTBS to lPMd and (3) iTBS to lPMd followed by BMT. This study tests three related hypotheses in three interventions: (1) BMT will enhance excitability within and between M1 bilaterally, (2) iTBS to left PMd will primarily enhance lM1 excitability, and (3) the combination of these interventions will cause a greater bilateral enhancement of M1 cortical excitability.

2.

Results

2.1.

Baseline measures and unconditioned stimuli

Baseline measures for all groups are shown in Table 1. Oneway ANOVAs were used to demonstrate that there were no significant differences in RMT, AMT and stimulator intensity used to deliver single and paired-pulse TMS. There were also no differences in baseline levels of MEPs, SICI, ICF, LICI, CSP or IHI. Finally, there were no differences between pre and post unconditioned stimuli during the paired pulse conditions to ensure the intracortical and interhemispheric excitability changes were not due to increases in unconditioned (single pulse) MEP amplitude.

2.2.

Analysis between groups

2.2.1.

Motor evoked potentials (MEPs)

Fig. 2 (bottom right panel) displays the average difference score between pre and post 30 min for MEP amplitudes from rM1 representation for all groups. There were no additive modulations of M1 excitability across any measures when combining iTBS to left PMd and BMT. However, there was a significant effect of GROUP for a change in rM1 MEP amplitude (F (2, 29)¼3.386, p ¼0.048). Post-Hoc analyses revealed that iTBS to left PMd alone caused a decrease and iTBS to left

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Table 1 – Baseline measures in all groups. LH ¼Left hemisphere; RH¼ Right hemisphere; SO¼Stimulator output; mV¼ millivolt; CS¼conditioning stimulus; ms¼ milliseconds; MEPs¼ motor evoked potentials; SICI¼ short-interval intracortical inhibition; ICF¼ intracortical facilitation; LICI¼ long-interval intracortical inhibition; CSP¼ cortical silent period; SIHI ¼short-interval interhemispheric inhibition; LIHI¼ long-interval interhemispheric inhibition. Baseline measures

LH RMT (%MSO) RH RMT (%MSO) AMT (%MSO) LH MEP (mV) RH MEP (mV) LH SICI (% CS) RH SICI (% CS) LH ICF (% CS) RH ICF (% CS) LH LICI (% CS) RH LICI (% CS) LH CSP (ms) RH CSP (ms) LH SIHI (% CS) RH SIHI (% CS) LH LIHI (% CS) RH LIHI (% CS)

Group 1 (mean7SE)

Group 2 (mean7SE)

Group 3 (mean7SE)

p value

40.671.9 41.871.9 N/A 1.170.2 0.870.1 46.778 47.777 152.9710.4 173.1712.1 16.477.5 28.277.5 131.877.8 132.676.5 69.775.3 64.876.3 71.576.8 68.975.9

42.471.8 42.771.9 39.172.1 0.870.2 0.770.2 57.278 49.576.7 168.9710 148.1712.1 23.877.8 27.076.9 129.278.2 127.476.9 70.674.9 62.776.3 65.576.2 79.975.7

42.171.8 43.871.8 39.472.1 0.670.2 0.670.2 58.277.6 58.676.7 155.9 79.6 142.2711.6 32.376.9 30.677.2 135.978.2 127.276.9 66.375.3 60.576.0 77.076.8 70.375.4

0.718 0.812 0.924 0.275 0.592 0.526 0.485 0.498 0.168 0.301 0.938 0.845 0.810 0.825 0.886 0.471 0.343

PMd followed by BMT caused a comparatively increased MEP amplitude in rM1 (p ¼0.045) (Fig. 2 – bottom right panel).

2.2.2.

Behavioral performance

Fig. 5 displays the behavioral data of groups 1 and 3, with the movement time (leftward panel) and angle at peak velocity (rightward panel). For movement time, a two-way ANOVA revealed a main effect of BLOCK (F (1, 24)¼ 27.071, po0.0001), no effect of GROUP (F (1, 24)¼ 0.007, p ¼0.935) and no interaction of BLOCK  GROUP (F (1, 24)¼ 0.081, p¼ 0.779). For angle at peak velocity, a two-way ANOVA revealed a main effect of BLOCK (F (1, 24)¼9.527, p ¼0.005), no effect of GROUP (F (1, 24)¼0.0003, p¼ 0.987), and no interaction of BLOCK  GROUP (F (1, 24)¼1.762, p¼ 0.201). The main effect of BLOCK indicates that there was a decrease in movement time and in deviation of cursor path from the initial to the final trials (i.e., performance improvement) similarly between groups 1 and 3.

Tables 2–3 show all means and statistical results of all groups. For group 1 (BMT), there was a trend towards a decreased ICF in rM1 in group 1 (BMT) (F (1, 11)¼ 4.703, p¼ 0.053) and a trend towards a decrease in LICI in lM1 (F (1, 11)¼ 3.422, p¼ 0.091). For group 3 (iTBS to left PMdþBMT – gray circles), there was a decrease in rM1 (F (1, 12)¼ 6.880, p¼ 0.022). In fact, for group 3, LICI was decreased to a similar extent in both hemispheres but was more consistent (less variable) in the right M1.

2.3.3.

Cortical silent period (CSP)

Fig. 4 (left panel) displays the average CSP duration for the left (top) and right (bottom) M1 ECR representations for all groups and Tables 2–3 show all means and statistical results. For group 1 (BMT), there was an increased duration in rM1 (F (1, 10)¼ 8.327, p¼ 0.016), and for group 2 (iTBS to left PMd), there was an increased duration in lM1 (F (1, 9)¼7.045, p¼ 0.026).

2.3.

Analysis within groups

2.3.4. Short (SIHI) and long-interval interhemispheric inhibition (LIHI)

2.3.1.

Motor evoked potentials (MEPs)

Fig. 4 (right panel) displays the average SIHI and LIHI for the right to left (top) and left to right (bottom) M1 ECR representations for group 1 (BMT) with Tables 2–3 showing all means and statistical results. For group 1 (BMT), there was a significant decrease from lM1 to rM1 (F (1, 9)¼6.602, p¼ 0.030).

Fig. 2 (left panel) displays the average MEP amplitudes for the left (top) and right (bottom) M1 ECR representations for all groups and Tables 2–3 shows all means and statistical results. For group 1 (BMT), there was an increase in amplitude in lM1 (F (1, 11)¼ 5.858, p¼ 0.034) and a trend of increased rM1 MEPs (F (1, 11)¼4.358, p¼ 0.061). For group 3, there was a trend towards an increase in rM1 (F (1, 9) ¼4.434, p¼ 0.065).

2.3.2. Short (SICI) and long-interval intracortical inhibition (LICI) and intracortical facilitation (ICF) Fig. 3 displays the average SICI and ICF data for the left (top) and right (bottom) M1 ECR representations for group 1 (BMT) (left panel) and average LICI data for the left (top) and right (bottom) M1 representation for all groups (right panel).

3.

Discussion

In this study, we investigated modulations of intracortical and interhemispheric M1 circuitry associated with the early phase of experience-dependent plasticity (i.e. in-phase BMT) that was preceded by iTBS to lPMd. The purpose of the iTBS was to enhance the excitability of a portion of the motor network involved in planning the trained coordinated

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Fig. 1 – Neuronavigation, experimental set up, and behavioral task. (A) TMS target locations. Template MRI from one session displaying the targets for TMS coil placement used for iTBS in left PMd (lPMd) and M1 bilaterally. A (anterior), P (posterior). (B) Above view of a participant performing the behavioral task, grasping the two handles and viewing both the target and cursor movement on the computer screen. (C) Displays movements made during the bimanual movement training task. Participants began in the bottom right corner and made varying degrees of wrist extension movements to move the cursor to the remembered visual targets. (D) Experimental Time Course. Graphic representation depicting the order of data collection and each experimental interventions. M1 (primary motor cortex), left PMd (left dorsal premotor cortex), iTBS (intermittent theta burst stimulation), BMT (bimanual training), 5 min post (bilateral collection of MEPs, SICI, ICF and IHI in group 2 only, immediately after iTBS to left PMd), 30 min post (bilateral collection of MEPs, SICI, ICF, LICI, CSP and IHI).

movements and measure these effects on the downstream bilateral M1. The unique modulations in M1 circuitry induced by short-term (in-phase) BMT preceded by iTBS to lPMd were primarily associated with changes in longinterval inhibitory mechanisms (i.e. GABAB-mediated). When BMT is preceded by iTBS to left PMd there is a slight increase in excitability along with a decrease in LICI in rM1. Short-term BMT alone was associated with increases in bilateral M1 excitability, with a decrease in LIHI from the left to right M1, and an increase in long-interval local inhibition in rM1 (i.e. increased CSP duration). Surprisingly, iTBS to lPMd alone was associated with an increase in longinterval local inhibition in lM1 (i.e. increased CSP duration). Collectively, these data suggest that BMT, iTBS to left PMd

and the combination of these interventions asymmetrically modulate the excitability and inhibitory circuitry within and between M1 representations.

3.1. The effects of iTBS to left PMd followed by bimanual training This study is the first to investigate the effects of applying iTBS to lPMd before BMT on the circuitry within and between M1. Specifically, we found a decrease in rM1 LICI and a slight increase in MEP amplitude due to iTBS to lPMd followed by short-term BMT. There is evidence that both the latter half of the CSP and LICI are associated with GABAB-like activity

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Fig. 2 – Motor evoked potentials (MEPs). Group-averaged MEP amplitudes from the left (top) and right (bottom) M1 ECR representation for all groups (left panels). Difference score (indicated by Δ) of MEP amplitudes for all groups from the rM1 representation (bottom right panel). Group 1: BMT (white circles), Group 2: iTBS to left PMd (black circles), Group 3: iTBS to left PMdþBMT (gray circles). Pre, 30 min post. Bars represent SE. Asterisk indicates significance, p r0.05.

Fig. 3 – Short (SICI) and long-interval intracortical inhibition (LICI) and intracortical facilitation (ICF). Group-averaged SICI and ICF from the left (top) and right (bottom) M1 ECR representation for group 1: BMT (left panels). Group-averaged LICI from the left (top) and right (bottom) M1 ECR representation for all groups (right panels). Group 1: BMT (white circles), Group 2: iTBS to left PMd (black circles), Group 3: iTBS to left PMdþBMT (gray circles). Pre, 5 min, and 30 min post. Bars represent SE. Asterisk indicates significance, p r0.05.

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Fig. 4 – Cortical silent period (CSP) and Interhemispheric inhibition (IHI). Group-averaged CSP from the left (top) and right (bottom) M1 ECR representation for all groups (left panels). Group-averaged short-interval IHI (SIHI) and long-interval IHI (LIHI) from the right to left (top) and left to right (bottom) M1 ECR representation for group 1: BMT (right panels). Group 1: BMT (white circles), Group 2: iTBS to left PMd (black circles), Group 3: iTBS to left PMdþBMT (gray circles). Pre, 30 min post. Bars represent SE. Asterisk indicates significance, pr0.05.

Fig. 5 – Behavioral data for groups 1 and 3. Left Movement time for Group 1 (white) and Group 3 (gray). Right Angle at peak velocity of the resultant cursor path for Group 1 (white) and Group 3 (gray). Bars represent SE. Asterisk indicates significance, pr 0.05. (Chen, 2004; Werhahn et al., 1999). The concurrent effects of slightly increased MEP amplitude and decreased LICI in the right hemisphere are consistent with the idea that increased presynaptic GABAB receptor inhibition is associated with decreased MEP amplitude (Chen, 2004; Sanger et al., 2001), where the current study found the reverse. Additionally, a recent study found that LICI decreased in a passively moved limb when movements of both limbs were symmetrical and there was a slight increase in LICI when movements were

asymmetrical (Byblow et al., 2012). These findings are consistent with the current findings of a decrease in LICI in rM1 when iTBS to lPMd was applied before BMT. Previous research has shown that the BMT performed in this study has shown increases in lateral premotor cortex (i.e. PMd) activity (Seitz et al., 2004) in both hemispheres (Smith and Staines, 2006, 2010, 2012). Therefore, pre-conditioning lPMd before BMT could have increased the neural input from the PM cortex to both the left and right M1, which in turn, caused an

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Table 2 – Statistical results. Displays statistical results for all ANOVAs performed within each group with factor time. LH ¼Left hemisphere; RH¼ Right hemisphere; MEP¼motor evoked potential; SICI¼ short-interval intracortical inhibition; ICF ¼intracortical facilitation; LICI¼ long-interval intracortical inhibition; CSP ¼cortical silent period; SIHI ¼short-interval interhemispheric inhibition; LIHI¼ long-interval interhemispheric inhibition. nindicates a trend toward significance, nn indicates significancepo0.05. Intervention Group 1: BMT LH MEP RH MEP LH SICI RH SICI LH ICF RH ICF LH LICI RH LICI LH CSP RH CSP LH SIHI RH SIHI LH LIHI RH LIHI

F F F F F F F F F F F F F F

(1, (1, (1, (1, (1, (1, (1, (1, (1, (1, (1, (1, (1, (1,

Group 2: iTBS to lPMd

11) ¼5.858, p ¼0.034** 11) ¼4.358, p ¼0.061 10) ¼0.390, p ¼0.546 10) ¼0.582, p ¼0.463 11)o0.0001, p¼ 0.995 11) ¼4.703, p ¼0.053* 11) ¼3.422, p ¼0.091 11) ¼0.617, p ¼0.449 10) ¼2.530, p ¼0.143 10) ¼8.327, p ¼0.016** 8) ¼0.043, p ¼0.840 11) ¼0.006, p ¼0.942 8) ¼0.253, p ¼0.629 9) ¼6.602, p ¼0.030**

F F F F F F F F F F F F F F

(2, (2, (2, (2, (2, (2, (1, (1, (1, (1, (2, (2, (2, (2,

Group 3: iTBS to lPMdþBMT

18) ¼ 0.852, p¼0.443 18) ¼ 2.414, p¼0.118 20) ¼ 0.682, p¼0.517 20) ¼ 2.373, p¼0.117 24) ¼ 1.075, p¼0.357 22) ¼ 0.477, p¼0.627 10) ¼ 0.118, p¼0.739 13) ¼ 0.559, p¼0.468 9) ¼ 7.045, p¼0.026** 9) ¼ 0.530, p¼0.485 22) ¼ 2.252, p¼0.129 22) ¼ 1.087, p¼0.355 22) ¼ 2.009, p¼0.158 20) ¼ 1.296, p¼0.296

F F F F F F F F F F F F F F

(1, (1, (1, (1, (1, (1, (1, (1, (1, (1, (1, (1, (1, (1,

9) ¼2.145, p ¼0.177 9) ¼4.434, p ¼0.065* 11) ¼0.816, p ¼0.386 11) ¼1.557, p ¼0.238 13) ¼0.140, p ¼0.714 12) ¼0.576, p ¼0.463 13) ¼1.377, p ¼0.262 12) ¼6.880, p ¼0.022** 9) ¼0.193, p ¼0.670 9) ¼0.014, p ¼0.909 9) ¼1.945, p ¼0.197 12) ¼2.816, p ¼0.119 9) ¼0.462, p ¼0.514 11) ¼1.226, p ¼0.292

Table 3 – Mean results. Displays all data for all groups and time points. LH¼ Left hemisphere; RH ¼Right hemisphere; MEP¼ motor evoked potential displayed in millivolts (mV); SICI¼short-interval intracortical inhibition; ICF¼ intracortical facilitation; LICI¼ long-interval intracortical inhibition; CSP ¼cortical silent period displayed in seconds; SIHI¼shortinterval interhemispheric inhibition; LIHI¼ long-interval interhemispheric inhibition. All paired pulse measures are displayed as a ratio of conditioned/unconditioned MEP. Displayed are means7standard error of the mean. Intervention BMT

LH MEP (mV) RH MEP (mV) LH SICI RH SICI LH ICF RH ICF LH LICI RH LICI LH CSP RH CSP LH SIHI RH SIHI LH LIHI RH LIHI

iTBS to lPMd

iTBS to lPMdþBMT

Pre

Post

Pre

Post

Pre

Post

1.170.3 0.770.2 0.4670.07 0.4970.08 1.5670.09 1.6870.02 0.1670.03 0.2870.05 13275.7 13373.7 0.7470.06 0.6570.05 0.7470.06 0.7270.06

1.770.8 1.070.2 0.5370.01 0.5270.06 1.4570.02 1.470.01 0.4870.07 0.2470.04 14076.6 14375.5 0.6870.08 0.6470.06 0.6970.06 0.8370.06

0.8170.18 0.6570.095 0.5770.08 0.4970.05 1.6970.13 1.4870.08 0.2470.08 0.2770.07 12979 12777.7 0.7070.04 0.6370.06 0.6670.06 0.8070.03

0.8870.28 0.5670.096 0.7370.21 0.6170.06 2.0270.027 1.6270.015 0.2970.014 0.3370.09 14079 12977.7 0.6570.08 0.7270.07 0.6270.08 0.7070.08

0.6870.13 0.5570.11 0.5870.082 0.5970.073 1.5670.07 1.4270.09 0.3270.084 0.3170.07 13679.1 12777.7 0.6670.05 0.6170.073 0.6970.06 0.7070.07

0.9070.19 0.8570.26 0.6570.01 0.6570.07 1.570.013 1.570.012 0.4770.01 0.5270.01 13378.7 12878.5 0.5570.08 0.7370.07 0.6870.09 0.7970.07

associated release of GABAB-related inhibition and increased excitability in the non-dominant ECR representation due to BMT. GABA-related inhibitory intracortical networks are implicated in the induction of cortical plasticity and reorganization following peripheral or central nervous system injury (Chen et al., 1998; Clarkson, 2012). Further, decreases in GABA-related inhibition are integral for motor learning and M1 cortical plasticity (Floyer-Lea et al., 2006; Stagg et al., 2011). Indeed, post-stroke motor disability is related to excessive GABArelated inhibition (Classen et al., 1997; Honaga et al., 2013; Takeuchi et al., 2010), and decreased GABA is key to the

recovery of function after stroke (Clarkson, 2012; Clarkson et al., 2010; Lazar et al., 2002). Since the current study did not measure GABA levels directly, it cannot be determined that a combination of iTBS to lPMd followed by BMT caused a decrease in GABA uptake or release. However, our results indicate that there is a reduction in long-interval intracortical inhibition after the combination of iTBS to lPMd and BMT, which is likely mediated by GABAB-related activity. These results have potential implications in aiding rehabilitation therapy after stroke. Along with the indication that stimulating PM areas to enhance cortical excitability may assist in neuroplastic recovery of ipsilesional motor areas (Cunningham et al., 2014; Plow et al.,

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2014, 2013), the current results of decreased LICI and concurrent increased excitability confirm and extend these ideas suggesting the potential benefit of rTMS to PM areas prior to motor training. Modulation of PM cortical areas (i.e. PMd) followed by rehabilitation training (e.g. BMT) could be advantageous in distinctly enhancing short-term plasticity in damaged M1 by decreasing excessive inhibition. Previously, it was found that iTBS over lPMd preceding inphase BMT led to a concurrent increase in the spatial distribution and overall amplitude of MEPs in lM1 (Neva et al., 2014b). Interestingly, an increase in spatial distribution and amplitudes of the total map in lM1 was seen due to a combination of iTBS over lPMd followed by BMT compared to either intervention alone (Neva et al., 2014b, 2012). The current study attempted to establish the potential intracortical and interhemispheric circuitry changes that may have contributed to the observed effects of iTBS and short-term BMT, and found that the effects were primarily in rM1 involving long-interval inhibitory circuitry. LICI has been shown to decrease with increased test stimulus intensity, which indicates that low threshold corticospinal neurons are more sensitive to LICI than high threshold corticospinal neurons (Sanger et al., 2001). It is possible that lower threshold corticospinal neurons in the area surrounding the hotspot were heightened in excitability due to the interventions, and were therefore activated during the testing of LICI. It could be that the modulation in LICI reflects a reduction in intracortical inhibition in the area surrounding the central representation of the specifically trained muscles, which would follow previous work (Neva et al., 2012, 2014a, 2014b).

3.2.

The effects of BMT

The current study found an increased MEP amplitude in lM1 and a trend to a significant increase in rM1. Enhancements in cortical excitability have been shown in several studies as an increase in the cortical area represented by the muscles involved in the trained task (Kleim et al., 1998, 2004; Nudo et al., 1996; Pascual-Leone et al., 1995) as well as increased MEP amplitudes at the motor hotspot (Liepert et al., 1999; Muellbacher et al., 2001; Pearce et al., 2000). For example, increases in the excitable cortical area in M1 have been observed after a 30 min session of BMT (Neva et al., 2012, 2014b) and skilled digit sequence training for two 2 h sessions (Pascual-Leone et al., 1995). Additionally, following training of skilled thumb movements, MEP amplitudes of the thumb muscle hotspot were enhanced compared to neighboring hand muscles (Liepert et al., 1999). Another study comparing spatial distribution and amplitudes of MEPs in the upper-limb representation between highly skilled racket players and non-skilled players showed that skilled racket players have not only the expected increased spatial distribution of MEPs compared to non-skilled players, but also have higher MEP amplitudes (Pearce et al., 2000). Modulation in MEP amplitude likely reflects overall excitability of the muscle representation and thus is an index of the sum of cortical and spinal motor output. Therefore, the current study indicates that the sum of corticospinal excitability of the trained muscle (ECR) representation was enhanced in left M1 and slightly increased in right M1 due to a single session of BMT.

This study found decreased IHI from the left to right M1 homologous representations due to BMT. It is thought that transcallosal activity between homologous M1 representations act to excite and/or release inhibition to the contralateral hemisphere after a bimanual task (Byblow et al., 2012; Stinear and Byblow, 2002), which could facilitate M1 excitability observed in the current and previous studies (Neva et al., 2012, 2014a, 2014b). Specifically, intracortical inhibition is decreased in M1 only when both upper-limbs are moving in a mirror-symmetrical pattern, where both agonist and antagonist muscles are activated simultaneously (Byblow et al., 2012; Stinear and Byblow, 2002). Also, following inphase active-passive movement training, inhibition between the homologous M1s (IHI) from the active to passive M1 is reduced (Byblow et al., 2012). The current results of decreased IHI only in one direction (non-dominant to dominant) may be initially surprising. However, this specific finding may be explained by the movement requirements of the BMT and laterality of IHI due to hand dominance. The BMT task required participants to perform simultaneous wrist extension movements of both upper-limbs to three different targets (351, 451, 551 relative to start position). The 451 target requires simultaneous co-contraction of the ECR muscles and to the same magnitude. However, the 351 and 551 target locations require a slightly different magnitude of cocontraction of both limbs. Therefore, the asymmetrical reduction in IHI could be due to the requirement of a different magnitude of co-contraction of the wrist muscles. Additionally, lateralization of M1, involving asymmetrically increased IHI from the dominant to non-dominant hemisphere (Bäumer et al., 2007; Netz et al., 1995; Sattler et al., 2012) may contribute to the decrease in IHI in one direction. A certain amount of IHI may have remained in order to assist in the differing amounts of co-contraction of the upper-limbs. This remainder of inhibition could have been more likely to suppress activity in the more experienced (dominant, right) upper-limb, leading to more stable IHI from the right to left M1. Inhibition may have been ‘released’ in order for the nondominant hemisphere to be more efficiently engaged during the complex bimanual movement task of the current study. Interestingly, we found a reduction in IHI only in longinterval IHI (LIHI, 40 ms ISI). The underlying mechanism mediating LIHI likely involves GABAB-mediated inhibition since it has a relatively longer time course and is increased with baclofen, a GABAB receptor agonist (Irlbacher et al., 2007). Also, a recent study has shown that LICI and LIHI are reduced when presented together in a series of paired pulses (Udupa et al., 2010), while SICI was unchanged in the presence of LICI or LIHI. This indicates that the GABAB mediated circuitry of LICI and LIHI work to suppress each other. These findings compliment the current finding of a slightly reduced LICI in lM1 (not significant), which may have in turn influenced the reduction of LIHI from the left to right hemisphere M1 due to the BMT in the current study. However, the specific claims on the interactions between LICI and LIHI inhibitory circuitry is only speculation, as further work would have to specifically test the interactions of these inhibitory circuits due to BMT and iTBS to lPMd. A session of BMT also induced an increased CSP duration in rM1. The excitability of cortical inhibitory networks within

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M1 is integral to motor control (Chen et al., 1999; Ljubisavljevic, 2006). Specifically, the ‘cortical silent period’ (CSP) duration is thought to indicate the state of cortical and spinal inhibitory networks (Chen et al., 1999; Inghilleri et al., 1993; Ljubisavljevic, 2006; Terao and Ugawa, 2002). Several studies suggest that the initial portion of the CSP is due to spinal mechanisms, and the latter portion due to longinterval cortical inhibition associated with GABAB-like mechanisms (Terao and Ugawa, 2002). Therefore, BMT in the present study could possibly increase GABAB inhibitory activity asymmetrically in the non-dominant (right) hemisphere, which may be associated with increased motor control required of the non-dominant hand, due to the slight varying magnitudes of co-contraction required for our BMT task. Of course, these speculations would have to be more systematically studied in order to delineate the associations of cortical inhibition and the skilled motor coordination required for our BMT task.

3.3.

The effects of iTBS to lPMd

This study found that iTBS to lPMd facilitated the inhibitory circuitry of ipsilateral lM1, in terms of longer CSP duration, which is seemingly contrary to the original hypothesis. PMd has extensive reciprocal neuronal projections with ipsilateral M1 (Picard and Strick, 2001; Rushworth et al., 2003). Perhaps iTBS increased the excitatory input from lPMd to ipsilateral M1 and, in turn, facilitated the long-interval inhibitory circuitry of the downstream M1. Other studies have shown that rTMS at 5 Hz to lPMd increases cortical excitability in the ipsilateral M1 (Chouinard et al., 2003; Gerschlager et al., 2001; O’Shea et al., 2007; Rizzo et al., 2004; Suppa et al., 2008). Further, cTBS over lPMd reduces MEP amplitudes from ipsilateral M1 with no changes in short-interval inhibitory or excitatory intracortical circuitry (Huang et al., 2009; Ortu et al., 2009). Huang and colleagues (2005) found that iTBS to M1 increases MEP amplitudes, later shown to be variable across participants potentially depending upon which interneuron populations are activated by TMS (Hamada et al., 2013). In addition, Huang et al. (2005) showed enhanced inhibitory circuitry, like SICI, due to iTBS to M1. However, unlike the current study, all of these studies mentioned above did not measure any effects on long-interval inhibitory mechanisms (i.e. LICI or CSP). It is possible that iTBS to lPMd selectively enhances inhibitory intracortical circuits in lM1 similarly to iTBS applied directly to M1. Perhaps this results from lPMd reciprocal connections with M1 in both hemispheres, with interactions between both excitatory and inhibitory projections, which may in turn also influence right M1 to left M1 projections (Asanuma and Okuda, 1962; Chen et al., 2003; Ferbert et al., 1992; Gerloff et al., 1998; Nelson et al., 2009), leading to an increased inhibition in lM1. Further, it could be that a facilitation in inhibitory activity in the center of the ECR representation, without a decrease in MEPs, could be indicative of a spatial increase in activity along the borders of the cortical representation, which would follow previous work (Neva et al., 2014b). The current results extends previous work demonstrating that GABAB-like cortical circuitry

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in M1 may be modulated by input from the upstream ipsilateral PMd. There are limitations that could affect the interpretation of the work. First, there were participants that took part in more than one experiment, with no one performing the BMT twice (experiments 1 and 3). The purpose of this was so that behavioral performance and therefore the potential cortical excitability changes were not confounded by the repetition of BMT. Second, a sham stimulation group was not tested for the specific effects of iTBS to lPMd alone and iTBS to lPMd followed by BMT. Therefore we did not test the placebo effects of training and stimulation. Finally, although training involved wrist flexion movements, as well as wrist extension, MEPs were not recorded from the flexor wrist muscles to observe the possibility of similar changes as observed in the wrist extensor muscles. Multiple single and paired pulse TMS measures were collected post intervention, with each post collection taking approximately 20–25 min. It is possible that the time window of after-effects of the interventions (BMT, iTBS to lPMd and iTBS to lPMdþBMT) were not fully captured due to the time constraints of collecting multiple measures. Future studies are needed to address the time-sensitive aftereffects of each intervention with regard to specific intracortical and interhemispheric measures.

4.

Conclusion

In sum, our findings suggest that iTBS to lPMd and BMT resulted in distinct modulations of M1 circuitry, which are associated primarily with changes in long-interval inhibitory (i.e. GABAB-like) neural mechanisms. Critically, this work may guide rehabilitation training and stimulation techniques that modulate cortical plasticity after brain injury and other neurological conditions. It may be that the modulation of remote cortical areas to M1 (i.e. PMd) in combination with rehabilitation training could be advantageous in distinctly enhancing short-term plasticity in damaged motor cortex. However, further study is required to understand the potential implications of this research that may be applicable in clinical settings.

5.

Experimental procedures

5.1.

Participants

Twenty-seven, self-reported right-handed participants (14 female; average age¼ 26 years,73.3) took part in the study. Participants were divided into 3 experiments with different interventions: BMT alone (group 1), iTBS to left PMd alone (group 2), and iTBS to left PMd followed by BMT (group 3). Thirteen participants were included in group 1 (BMT alone) and 14 different individuals participated in groups 2 and 3 in random order, and these experiments were separated by at least one week. The purpose for the separate individuals in group 1 and 3 was primarily to avoid the performance the same in-phase BMT task twice. The experimental procedures were approved by the University of Waterloo Office of Research Ethics. All participants provided informed written

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consent and completed a TMS screening form (Keel et al., 2000).

5.2.

Electromyographic (EMG) recording

Surface EMG was recorded from the left and right extensor carpi radials (ECR) muscle using 9 mm diameter Ag–AgCl electrodes. Two active electrodes were placed over the muscle belly of the left and right ECR with a ground electrode over the right styloid process of the ulna. EMG recordings were amplified (1000  ), band-pass filtered (2–2500 Hz) (Intronix Technologies Corporation Model 2024F, Canada), digitized at a sample frequency of 5 kHz by an analog-to-digital interface (Micro1401, Cambridge Electronics Design, Cambridge, UK), and stored for later analysis.

5.3.

TMS & neuronavigation

Single and paired-pulse TMS was delivered using two custom built 50 mm inner diameter figure-of-eight branding coils connected to two Magstim 2002 stimulators (Magstim, Whitland, UK). TBS was applied using a 90 mm outer diameter figure-of-eight coil with a MagPro stimulator (MCF-B65; Medtronic, Minneapolis, MN, USA). BrainSight Neuronavigation (Rogue Research, Canada) was used to guide the coil to the cortical target areas using a template MRI for all participants. The motor hotspot for the ECR in M1 bilaterally was acquired by placing the stimulation coils on the scalp at a 451 angle to the mid-sagittal plane. The motor hotspot was determined to be the location in both M1s to elicit an optimal MEP in the contralateral resting ECR. The resting motor threshold (RMT) was defined as the lowest stimulus intensity that would elicit 5 out of 10 MEPs greater than or equal to a peak-to-peak amplitude of 50 mV (Rossini et al., 1994) using the MagStim stimulator. The active motor threshold (AMT) was defined as the lowest stimulus intensity that would elicit 5 out of 10 MEPs greater than or equal to a peak-to-peak amplitude of 200 mV while maintaining a 10% maximum voluntary contraction (MVC) of the right ECR, and while holding the MagPro stimulator over the optimal ECR representation in left M1. For iTBS, the theta burst pattern of stimulation (three stimuli delivered at 50 Hz, which were grouped and delivered at 5 Hz) was delivered in blocks of 2 s followed by a period of 8 s with no stimulation, for a total of 600 stimuli applied over 190 s (Huang et al., 2005; Stinear et al., 2009). We delivered iTBS to PMd in the left hemisphere (Huang et al., 2005; Stinear et al., 2009) at 80% of AMT with the coil at a posterior-medial orientation (handle backwards). The location of PMd was determined to be 2.5 cm anterior to the ECR motor hotspot in left M1 (Huang et al., 2009; Neva et al., 2014b; Picard and Strick, 2001). For all groups, measurements were obtained from the left and right ECR before and following BMT and/or iTBS to left PMd, with group 2 having measurements obtained immediately after iTBS to left PMd and 25–30 min post. Each collection of single and paired pulse measurements took 20– 25 min. The order of right versus left hemisphere stimulation was randomized across participants. Background EMG activity of the right and left ECR muscle was quantified during the ISI between M1 stimulation, which did not exceed 25 mV, otherwise the sample trial was discarded.

5.4.

Behavioral task

Participants were seated in a well lit room facing an LCD monitor positioned 70 cm in the vertical plane in front of the participant. The medial aspects of bilateral forearms were supported with elbows flexed to 901 and shoulders in forward flexion  0–101. Flexion and extension of the wrist occurred in the horizontal plane. Participants grasped two separate handles of a custom-made device that was placed on a table (Fig. 1B C). The handles of the device pivoted in clockwise and counter-clockwise directions and were linked to two separate potentiometers (sampled at 100 Hz) within the device structure. The custom-made device, in conjunction with a customized program written in LabVIEW (National Instruments, Austin, TX), allowed the participants to control a cursor on a LCD monitor by flexing and extending the wrists while gripping the handles of the device. Right wrist extension controlled upward movement of the cursor, and right wrist flexion controlled downward movement of the cursor. Left wrist extension controlled leftward movement of the cursor, and left wrist flexion controlled rightward movement of the cursor. Each participant's range of motion performed during the BMT task was calibrated to each individuals  90% maximum flexion and extension range of motion, which was not limited by an injury or condition (e.g. arthritis). BMT consisted of 160 bimanual wrist extension movements (lasting 25–30 min) to visually cued targets displayed on an LCD monitor (Fig. 1B and C) (Neva et al., 2012, 2014a, 2014b). Participants were required to make simultaneous in-phase wrist extension movements that moved a cursor to targets displayed in the upper left from the lower right (starting point) quadrants of the computer screen (Fig. 1C). Targets were displayed as a box outlined in black (2.5  2.5 cm), and appeared at one of three different locations in the upper-left corner of the screen in pseudo-random order for 500 ms and then disappeared, after which participants waited during a 2 s preparation period. After 2 s, the cursor reappeared and a brief bimanual wrist extension movement was made to the remembered target location. A 2 s time window was provided in order to move the cursor to the desired target. If the cursor did not reach the target within 2 s it was considered an incomplete trial.

5.5.

Procedure

5.5.1.

Group 1: BMT

Thirteen participants (7 female; average age¼ 28 years,73) performed a short-term session of in-phase BMT (Neva et al., 2012, 2014a, 2014b). MEPs, short-interval intracortical inhibition (SICI), intracortical facilitation (ICF), long-interval intracortical inhibition (LICI), cortical silent period (CSP) duration and interhemispheric inhibition (IHI) were recorded from the ECR bilaterally before and immediately after BMT in a pseudo-random order, as depicted in Fig. 1D. For MEPs, 15 single TMS pulses were applied over the left and right M1. TMS intensity was set at 120% of RMT for both the left and right M1 ECR representation. For SICI and ICF, both the conditioning and test stimuli were applied over M1 with the same coil connected to a Magstim 2002 stimulator operating via a Bistim module. SICI and ICF were performed with a subthreshold conditioning stimulus (CS) followed by a suprathreshold test

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stimulus (TS) to the M1 hotspot for ECR. The interstimulus interval (ISI) for SICI and ICF was 3 and 10 ms respectively, to produce intracortical inhibition and facilitation (Di Lazzaro et al., 2006; Kujirai et al., 1993). To measure SICI and ICF, a block of TMS pulses consisted of TS alone, ISI of 3 ms (SICI) and ISI of 10 ms (ICF). Each ISI and TS alone trials were randomly presented 15 times during the pre and post collections, with an inter-trial interval of 6 s. The CS was set at 80% of RMT for SICI and ICF, which was determined before BMT and kept consistent throughout the experiment. The maximum stimulator output of the TS intensity was adjusted to consistently evoke MEPs in the contralateral ECR of 0.3–0.5 mV before and after BMT (Perez and Cohen, 2008). LICI was elicited by suprathreshold CS and TS with an ISI of 100 ms (Chen, 2004; Chen et al., 1999; Inghilleri et al., 1993; Nakamura et al., 1997) over M1 ECR representation, which were both adjusted to consistently evoke MEPs in the contralateral ECR of 0.3–0.5 mV throughout the experiment. IHI was tested in both cortical directions (left M1-right M1 and vice versa), with the CS and TS adjusted to consistently evoke MEPs in the contralateral ECR of 0.3–0.5 mV. The ISIs for IHI were 10 and 40 ms, to produce short and long IHI (SIHI and LIHI), respectively (Chen et al., 2003; Chen, 2004; Ferbert et al., 1992; Nelson et al., 2009; Perez and Cohen, 2008). Similarly to SICI and ICF, a block of TMS pulses consisted of TS alone and ISIs of 10 ms (SIHI) and 40 ms (LIHI). Each ISI and TS alone trials were randomly presented 15 times during the pre and post collections. Finally, CSP duration (Terao and Ugawa, 2002) was tested with participants maintaining a 20% MVC of the contralateral ECR and fifteen single pulses of TMS were applied to the left and right M1 at an intensity of 130% RMT. The duration of the CSP was acquired from the TMS stimulus onset to the re-onset of muscle activity within the ECR muscle.

5.5.2.

Group 2: iTBS to left PMd

Fourteen participants (7 female; average age¼24 years,74) received iTBS over left PMd at 80% of AMT (Huang et al., 2009; Neva et al., 2014b; Stinear et al., 2009). MEPs, SICI, ICF, LICI, CSP and IHI were recorded from ECR bilaterally using the same methodology as in group 1, with the addition of collection immediately after iTBS to left PMd including MEPs, SICI, ICF and IHI in M1 bilaterally. This was then followed by recording all of the dependent measures as in group 1 at 30 min post iTBS to left PMd.

5.5.3.

Group 3: iTBS to left PMd followed by BMT

The same fourteen individuals in group 2 (7 female; average age¼ 24 years,74) received iTBS over left PMd at 80% of AMT (Huang et al., 2009; Neva et al., 2014b; Stinear et al., 2009), which was followed by the same in-phase BMT performed by group 1. All dependent measures were recorded using the same methodology and at the same time intervals as in group 1.

5.6.

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pre and post 30 min time points with between-subjects factor GROUP (Group 1: BMT, Group 2: iTBS to left PMd, Group 3: iTBS to left PMdþBMT). Additionally, to specifically investigate the temporal factors of each intervention, analysis was performed within each group across all time points. Therefore, for groups 1 and 3 a one-way repeated measures analysis of variance (ANOVA) was used with within-subject factor TIME (2 levels: pre, post) for each dependent measure (MEPs, SICI, ICF, LICI, CSP and IHI) for the left and right ECR. For group 2, a one-way repeated measures ANOVA was performed using within-subject factor TIME (3 levels; pre, post 1 min and post 30 min) for each dependent measure as in groups 1 and 3. Additionally, post-hoc analyses were performed with the Tukey correction method to investigate any other differences between time points. Significance was set at pr 0.05. Individuals that did not display the expected inhibition or facilitation with the baseline paired pulse (SICI, ICF, LICI, or IHI) measures were not included in that particular analysis. Behavioral performance for groups 1 and 3 was quantified in terms of the movement time for both hands and the resultant cursor movement to the targets displayed on the screen. Generally, both hands were active simultaneously and were similarly contributing to the resultant cursor movement across training trials in both groups. Specifically, the behavioral performance was quantified by taking the movement time and the angle at peak velocity of the resultant cursor path (wrist extension movements of both upper-limbs) relative to an ideal (straight) path to the visual target, for each movement trial (Neva et al., 2012, 2014b). A two-way ANOVA was performed on the movement time and angle at peak velocity including within-subjects factor BLOCK (first block and last block of 10 trials) and between-subjects factor GROUP (BMT and iTBS to left PMdþBMT). Where appropriate, post-hoc analyses were performed with Tukey's correction method to investigate potential differences between interventions. Significance was set at p r0.05.

Acknowledgments This work was supported by funding to WRS from the Natural Sciences and Engineering Research Council of Canada (NSERC) and the Canada Research Chairs program. JLN was supported by graduate scholarship funds from the Ontario Graduate Scholarship (OGS) Program. M.V. was supported by postdoctoral funding from the Heart and Stroke Foundation Center for Stroke Recovery, Sunnybrook Health Science Center and the Ministry of Research and Innovation, Province of Ontario.

r e f e r e nc e s

Statistical analysis

To investigate whether the combination of iTBS to left PMd and BMT would possibly yield additional modulations of intracortical and interhemispheric M1 excitability compared to either intervention alone, a one-way ANOVA was performed across all groups with the difference score between

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