Priming sensorimotor cortex to enhance task-specific training after subcortical stroke

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Clinical Neurophysiology xxx (2013) xxx–xxx

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Clinical Neurophysiology journal homepage: www.elsevier.com/locate/clinph

Priming sensorimotor cortex to enhance task-specific training after subcortical stroke Suzanne J. Ackerley a,c, Cathy M. Stinear b,c, P. Alan Barber c,d, Winston D. Byblow a,c,⇑ a

Movement Neuroscience Laboratory, Department of Sport and Exercise Science, The University of Auckland, Auckland, New Zealand Clinical Neuroscience Laboratory, Department of Medicine, The University of Auckland, Auckland, New Zealand c Centre for Brain Research, The University of Auckland, Auckland, New Zealand d Neurology Department, Auckland City Hospital, Auckland, New Zealand b

a r t i c l e

i n f o

Article history: Accepted 23 November 2013 Available online xxxx Keywords: Sensorimotor integration Short latency afferent inhibition Stroke rehabilitation Theta burst stimulation Transcranial magnetic stimulation

h i g h l i g h t s  The effects of Theta Burst Stimulation (TBS)-primed dexterity training on sensorimotor integration,

corticomotor excitability, sensation and grip-lift kinetics were examined in chronic subcortical stroke patients.  Intermittent TBS (iTBS) of ipsilesional primary motor cortex (M1) modulated corticomotor excitability and increased M1 receptiveness to sensory input.  Priming ipsilesional M1 with iTBS prior to upper limb therapy may facilitate sensorimotor integration and serve as a useful adjunct to improve the quality of sensorimotor training during rehabilitation after subcortical stroke.

a b s t r a c t Objective: This double-blind sham-controlled crossover study investigated the interactions between primary sensory and motor cortex after stroke and their response to Theta Burst Stimulation (TBS). Methods: Thirteen chronic subcortical stroke patients with upper limb impairment performed standardised dexterity training primed with ipsilesional M1 intermittent TBS (iTBSiM1), contralesional M1 continuous TBS (cTBScM1) or sham TBS. The effects on sensorimotor integration, corticomotor excitability, sensation and grip-lift kinetics were examined. Results: After iTBSiM1, improvements in paretic grip-lift performance were accompanied by an immediate facilitation of ipsilesional M1 excitability and a subsequent increase in ipsilesional short latency afferent inhibition (SAI) during training. Precision grip-lift performance improved after cTBScM1 and training, alongside increased ipsilesional M1 excitability with no effect on ipsilesional SAI. There were no effects on sensory performance. Conclusion: Primary motor cortex iTBS not only modulates M1 corticospinal excitability but also increases M1 receptiveness to sensory input. Significance: Priming with iTBSiM1 may enhance ipsilesional sensorimotor integration and facilitate better quality sensorimotor training after subcortical stroke. Ó 2013 Published by Elsevier Ireland Ltd. on behalf of International Federation of Clinical Neurophysiology.

1. Introduction Paretic upper limb impairment after subcortical stroke may be compounded by a cycle of asymmetric primary motor cortex (M1) excitability and interhemispheric inhibition, which in turn

⇑ Corresponding author. Address: Movement Neuroscience Laboratory, Centre for Brain Research, The University of Auckland, Private Bag 92019, Auckland, New Zealand. Tel.: +64 9 373 7599x86844; fax: +64 9 373 7043. E-mail address: [email protected] (W.D. Byblow).

exacerbates ipsilesional M1 hypoexcitability and contralesional M1 hyperexcitability (Heald et al., 1993; Traversa et al., 1998; Shimizu et al., 2002; Murase et al., 2004; Duque et al., 2005). Repetitive transcranial magnetic stimulation (rTMS) has been used to rebalance M1 excitability in stroke patients (Takeuchi et al., 2005; Fregni et al., 2006; Talelli et al., 2007a; Di Lazzaro et al., 2008) and has been associated with better motor outcomes (for a review see Hsu et al., 2012). Intermittent and continuous theta burst stimulation (iTBS, cTBS) are protocols of patterned rTMS (Huang et al., 2005) that

1388-2457/$36.00 Ó 2013 Published by Elsevier Ireland Ltd. on behalf of International Federation of Clinical Neurophysiology. http://dx.doi.org/10.1016/j.clinph.2013.11.020

Please cite this article in press as: Ackerley SJ et al. Priming sensorimotor cortex to enhance task-specific training after subcortical stroke. Clin Neurophysiol (2013), http://dx.doi.org/10.1016/j.clinph.2013.11.020

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S.J. Ackerley et al. / Clinical Neurophysiology xxx (2013) xxx–xxx

can be applied to increase ipsilesional M1 excitability (Talelli et al., 2007a; Di Lazzaro et al., 2008, 2010; Ackerley et al., 2010) or decrease contralesional M1 excitability (Talelli et al., 2007a; Di Lazzaro et al., 2008), respectively. Suppressive rTMS of contralesional M1 may facilitate ipsilesional M1 excitability by reducing transcallosal inhibition from contralesional to ipsilesional M1 (Kobayashi et al., 2004; Takeuchi et al., 2005). However it is becoming evident that cTBS effects on M1 excitability are more variable than iTBS effects (Ackerley et al., 2010; Martin et al., 2006; Gentner et al., 2008). Despite this, in patients with upper limb impairment at the chronic stage after subcortical stroke, both ipsilesional M1 iTBS and contralesional M1 cTBS can improve griplift performance when combined with dexterity training with the paretic hand (Ackerley et al., 2010). During rehabilitation after stroke, sensorimotor training produces afferent input to M1, which shapes and focuses descending commands (Kaelin-Lang et al., 2005). Impairments in sensorimotor integration during prehension have been observed after subcortical stroke (McDonnell et al., 2006). These impairments arise through deficient motor control and somatosensory deficits (Johansson and Westling, 1984; Nowak et al., 2001; Smania et al., 2003; Blennerhassett et al., 2007). Abnormal sensorimotor integration is common in patients with lesions involving sensorimotor cortex, basal ganglia or the cerebellum (Wiesendanger and Serrien, 2001; Sailer et al., 2003; Oliviero et al., 2005; McDonnell et al., 2006; Di Lazzaro et al., 2012). Here we investigated whether TBS makes M1 more receptive to sensory input during sensorimotor training by measuring TBS after effects on short latency afferent inhibition (SAI) (Tokimura et al., 2000). The aim of this study was to elucidate the neurophysiological mechanisms that contribute to improvements in prehension after TBS-primed dexterity training. We applied iTBS to ipsilesional M1 (iTBSiM1), cTBS to contralesional M1 (cTBScM1) or sham TBS in separate sessions. Based on previous findings (Ackerley et al., 2010), we expected that real but not sham TBS combined with dexterity training with the paretic hand would improve grip-lift

kinetics. We hypothesised that ipsilesional M1 excitability would be directly facilitated by iTBSiM1, but that the iTBSiM1 and cTBScM1 protocols would have differential effects on ipsilesional sensorimotor integration evident in SAI. 2. Methods 2.1. Participants Thirteen adults with persistent upper limb impairment after first-ever subcortical stroke at least 6 months previously participated in this double-blind, sham-controlled, cross-over study. Volunteers were excluded if they had contraindications to TMS, were on medications that interfered with the interpretation of the neurophysiological results, had motor evoked potential (MEP) amplitudes less than 0.05 mV in the paretic first dorsal interosseous muscle (FDI), or had moderate or severe sensory loss of the paretic arm (National Institutes of Health Stroke Scale (NIHSS) sensory subscale > 1). Written informed consent was provided by all participants and the study was approved by the regional ethics committee in accordance with the Declaration of Helsinki (1964). Participants attended an introductory session where clinical assessments were performed (Table 1), and sensory and precision grip assessments, and the Action Research Arm Test (ARAT, maximum 57) (Lyle 1981) of the nonparetic upper limb were completed. FDI MEPs were examined to determine the interstimulus interval (ISI; 25, 30, or 40 ms) that produced the most SAI in the contralesional M1 (i.e. optimal ISI), using the paired pulse methods described below. 2.2. Experimental sessions The three experimental sessions were randomised, counterbalanced and separated by at least 1 week (see Fig. 1 for a flowchart of the experimental procedures). Each session consisted of a TBS

Table 1 Participant Characteristics. No.

Sex

Age (years)

Time since stroke (months)

NIHSS (max 42)

NIHSS sensory subscale

FM (max 66)

mRS

ASH

Hand

9HT (sec/peg)

Hemi

Type

1 2a 3

M M M

61 83 58

34 17 22

4 2 2

1 0 0

53 44 37

2 4 2

61 0 63

L R R

1.92 >60 20.0

L L R

I I H

4 5 6 7b 8 9

F M F F M F

68 70 71 78 56 65

7 6 41 54 32 36

2 5 4 6 3 4

0 0 1 1 0 1

51 28 27 55 53 42

1 3 2 3 2 2

0 63 63 0 0 62

R R R R R R

1.69 >60 >60 >60 2.40 7.50

R R R R L R

I I H I I I

10

F

69

11

5

1

25

4

63

R

>60

R

I

11 12c 13b

F M M

79 68 31

6 32 7

4 3 3

0 0 0

46 31 54

2 1 2

0 61 0

R L R

>60 30.0 1.90

R L R

I H I

69 8 83 56

23 16 54 6

4 1 6 2

41 11 55 25

2 1 4 1

Mean SD Max Min

Affected structures BG

Ca, Pu Th

Capsule

Other

Cr Int Int Cr Pontine Int Cr

Cr

MCA territory MCA territory SCWM SCWM

NIHSS sensory subscale (normal = 0, mild/moderate sensory loss = 1). FM = Fugl-Meyer upper limb score. mRS = modified Rankin Score. ASH = Modified Ashworth Scale tested in paretic biceps brachii, wrist and finger flexors. 9HT = Nine hole peg test. Hand = handedness prior to stroke. Hemi = hemisphere affected by the stroke. Type (Ischaemic/ Haemorrhagic). Affected Structures: BG = basal ganglia; Pu = putamen; Th = thalamus; Ca = caudate; Cr = Corona radiata; Int = internal capsule. MCA territory = Middle cerebral artery territory; SCWM = Subcortical white matter. a This patient had a longstanding arthritic condition affecting both hands. b Unable to access CT scans. c Patient did not complete all sessions, data not included in summary statistics.

Please cite this article in press as: Ackerley SJ et al. Priming sensorimotor cortex to enhance task-specific training after subcortical stroke. Clin Neurophysiol (2013), http://dx.doi.org/10.1016/j.clinph.2013.11.020

S.J. Ackerley et al. / Clinical Neurophysiology xxx (2013) xxx–xxx

protocol (iTBSiM1, cTBScM1 or sham TBS) followed by standardised sensorimotor training with the paretic upper limb. Neurophysiological, sensory and precision grip assessments of the paretic hand were completed before and after TBS and training. Paretic upper limb function was assessed with the ARAT at the beginning and end of each session by a clinical assessor blinded to the TBS protocol. 2.2.1. Theta burst stimulation Theta burst stimulation (600 stimuli) was applied over either M1 with a biphasic Rapid Stimulator (Magstim, Dyfed, UK) by an investigator blinded to all other aspects of data collection and analysis. Patients were blinded to the TBS protocol. TBS intensity was set to 90% active motor threshold (AMT) of the nonparetic FDI (Ackerley et al., 2010). Intermittent TBSiM1 was delivered to induce current in the brain in a posterior to anterior direction. Continuous TBScM1 was delivered to induce current in the brain in an anterior to posterior direction, which preferentially targets early I-waves (Di Lazzaro et al., 2005; Talelli et al., 2007b). Sham TBS

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(intermittent or continuous, counterbalanced) was delivered to either M1 with a sham coil (Magstim, Wales UK). 2.2.2. Dexterity training Sensorimotor training of the paretic upper limb commenced 20 min after TBS and consisted of 4 blocks of precision grip movements each lasting 4 min. Participants were required to pick up cylindrical pegs, insert them into 9 holes in a standardised pegboard, and then remove them one at a time. The number of pegs moved in each block was recorded. 2.2.3. Neurophysiological assessment Measures of corticomotor excitability (CE) and sensorimotor integration (SAI) were obtained from MEPs recorded with surface electromyography (EMG) from resting FDI bilaterally. Electrodes (15 mm Ag–AgCl, Ambu A/S, Ballerup, Denmark) were positioned in a belly-tendon montage following standard skin preparation techniques. EMG was amplified (CED 1902, Cambridge, UK), band-pass filtered (2–1000 Hz), sampled at 2 kHz using Signal

Fig. 1. Flowchart of the experimental procedures. In the experiment, gray shading indicates components that require voluntary muscle contraction. ARAT = Action Research Arm Test, SAI = Short latency afferent inhibition. MEPs = Motor evoked potentials measured from bilateral first dorsal interosseous (FDI). SENSORY = sensory assessment. TRAIN represents the four training blocks.

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4.07 software (CED 1401, Cambridge, UK) and stored for offline analysis. TMS was applied using a 70 mm figure-of-eight coil connected to a Magstim 200 magnetic stimulator (maximum output intensity 2.0 T, Magstim, Dyfed, UK). The optimal position (hotspot) on each side of the scalp to evoke a MEP from contralateral FDI was marked to ensure consistent coil placement. Rest motor threshold (RMT) was defined as the minimum stimulus intensity that produced a peak-to-peak MEP amplitude P50 lV in FDI in four of eight consecutive trials (Rossini et al., 1994). TMS was either nonconditioned (NC) or conditioned (C) by electrical cutaneous stimulation at the optimal ISI for obtaining SAI for each participant determined in the introductory session. Electrical cutaneous stimulation (Digitimer, Constant Current DS7A, UK) was delivered to the index finger via ring electrodes (Digitimer, UK) with cathode and anode placed around proximal and middle phalanges respectively. Stimulation consisted of an electrical square wave pulse (1 ms) delivered at an intensity of two times perceptual threshold (Classen et al., 2000; Tamburin et al., 2001). Stimulation intensity was set to produce an MEP that was 50% of the maximum MEP amplitude (50%MEPmax) to maintain sensitivity to both increases and decreases in corticomotor excitability (Devanne et al. (1997)) as well as an accurate measure of SAI (Udupa et al., 2009). Sixteen C and 16 NC MEPs were collected in a randomised order at each time point. At POST18 only NC MEPs were collected as a measure of corticomotor excitability before training started (POST20). Peak-to-peak MEP amplitude (mV) was obtained in a 20 ms window relative to the MEP onset for each muscle. Average C and NC MEP amplitudes were determined for each time point. SAI (%) was calculated as SAI (%) = 100 [(C/NC)  100], such that larger values indicated more inhibition. The root mean square (rms) value of pre-trigger EMG activity (rmsEMG) was determined in a 50 ms window preceding the conditioning stimulus to ensure muscle quiescence. Trials were rejected offline when pre-trigger rmsEMG exceeded 15 lV in either FDI.

2.2.4. Sensory assessment For all sensory testing participants sat with their hand positioned comfortably in supination and their eyes closed. Spatial acuity threshold (mm) was evaluated in the pads of the index finger and thumb using the grating orientation task (Bleyenheuft and Thonnard, 2007). Grating domes (8 grate widths ranging from 0.35 to 3.0 mm) were pressed onto the pad for 1.5 s with the grooves oriented parallel (‘‘along’’) or perpendicular (‘‘across’’) to the long axis of the digit (JVP Domes., Stoelting Co., Wood Dale, IL). Eight trials were performed in decreasing order, and grate widths with 75% correct responses were determined. Spatial acuity threshold (mm) was calculated as WS + [(WL WS)  (0.75 PS)/(PL PS)] where WS is the smallest groove width that the participant responded to with P75% accuracy, WL is the largest groove width that the participant responded to with 0.05) and pooled across sessions for comparison with the nonparetic hand (Table 2). At baseline paretic upper limb function (ARAT) was reduced and precision grip kinetics (PD and PF) were impaired compared to the nonparetic side (all P < 0.05). MEP measures indicated that corticomotor excitability and SAI

Please cite this article in press as: Ackerley SJ et al. Priming sensorimotor cortex to enhance task-specific training after subcortical stroke. Clin Neurophysiol (2013), http://dx.doi.org/10.1016/j.clinph.2013.11.020

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were lower in the paretic compared to the nonparetic FDI (both P < 0.01), consistent with previous findings (Di Lazzaro et al., 2012). There was no difference between hands in pain threshold, spatial acuity threshold or cutaneous sensory threshold (all P > 0.1) (see Table 2). Stimulation parameters and the amount of training did not differ between sessions (all P > 0.2) (Table 3). As expected, a higher RMT was noted for the ipsilesional M1.

after cTBScM1, MEP amplitudes increased once training commenced, at POST29 and POST48 (one-sample t-tests, both P < 0.02), but not after sham (one-sample t-tests, all P > 0.4). For nonparetic FDI, there was a main effect of PROTOCOL (F2,22 = 4.57, P = 0.022). Paired t-tests indicated no difference in MEP amplitude after iTBSiM1 or cTBScM1 when compared with sham (P > 0.1). MEP amplitude was reduced compared with baseline only after iTBSiM1 (one-sample t-test, t11 = 2.56, P = 0.026).

3.2. Main experiment

3.2.2. Sensory assessment There were no main effects of PROTOCOL or TIME, or interactions (all P > 0.05) for any sensory assessment measures.

SAI: For paretic FDI, there was a main effect of PROTOCOL (F2,16 = 4.21, P = 0.034) and TIME (F2,16 = 4.62, P = 0.026). The main effect of PROTOCOL was explored by collapsing across TIME. SAI was greater after iTBSiM1compared to sham (paired t-test, t8 = 2.47, P = 0.039) and baseline (one-sample t-test, t8 = 3.60, P = 0.007) (Fig. 2A). After cTBScM1, SAI did not differ from sham (paired t-test, P > 0.8) and neither differed from baseline (one-sample t-tests, both P > 0.8). The main effect of TIME was explored by collapsing across PROTOCOL. SAI was greater at POST29 compared to POST48 (paired t-test, t8 = 3.09, P = 0.015) and baseline (onesample t-test, t8 = 2.86, P = 0.021). For nonparetic FDI, there was a main effect of PROTOCOL (F2,22 = 3.57, P = 0.046) and TIME (F2,22 = 4.04, P = 0.032). Collapsing across TIME, there were no differences between SAI after iTBSiM1 or cTBScM1 compared with sham (paired t-tests, P > 0.05), or after any protocol compared to baseline (one-sample t-tests, P > 0.1). Collapsing across protocol, SAI decreased at POST29 compared to POST5 and POST48 (both P < 0.04), but was not different from baseline (P > 0.1). 3.2.1. MEP amplitude For paretic FDI, there was a PROTOCOL  TIME interaction (F6,66 = 3.21, P = 0.008). This interaction was decomposed for each protocol with one-way ANOVAs for the factor TIME. After iTBSiM1 there was an effect of TIME (F3,33 = 4.90, P = 0.006) (Fig. 2B). At POST5, MEP amplitude was facilitated compared to the subsequent time-points (paired t-tests, all P < 0.05) and compared with baseline (one-sample t-test, t11 = 2.55, P = 0.027). MEP facilitation above baseline did not persist after paretic hand movement (one sample t-tests, all P > 0.045, n.s. after correction). After cTBScM1 and sham TBS there was no effect of TIME (both P > 0.1). However

3.2.3. Grip-lift kinetics For preload duration (PD), the PROTOCOL x TIME interaction (F4,44 = 3.05, P = 0.027) was decomposed for each protocol with one-way ANOVAs for the factor TIME. There was no effect of TIME after iTBSiM1 (F2,22 = 1.25, P > 0.3) or cTBScM1 (F2,22 = 2.44, P > 0.1). However at POST35, PD was decreased compared to baseline after iTBSiM1 (79.6 ± 1.3%) and cTBScM1 (81.1 ± 8.2%) (one-sample t-tests, both P < 0.05). An effect of TIME was observed after sham TBS (F2,22 = 4.42, P = 0.024). PD was decreased immediately after sham TBS at POST11 (86.4 ± 3.1%) (one-sample t-test, t11 = 5.46, P < 0.001), but increased after subsequent training (POST54, 104.0 ± 6.9%) (paired t-test, t11 = 2.78, P < 0.02). There were no main effects or interactions for preload force (PF, all P > 0.1). 3.2.4. Upper limb function There were no effects of PROTOCOL or TIME on ARAT scores (all P > 0.1). 3.2.5. Regression analyses Regression analyses were conducted to explore associations between DCEcM1 (% change from PRE) and DCEiM1 (% change from PRE) at POST5 and baseline clinical scores (NIHSS, ARAT, FM, PD). There was no association between DCEiM1 at POST5 and any baseline clinical score (all R2 < 0.33, P > 0.05) (Fig. 2C). There was a strong positive correlation between the immediate DCEcM1 and NIHSS (R2 = 0.65, P = 0.002) (Fig. 2D). Patients with more severe strokes had less suppression of contralesional M1 excitability after cTBScM1. There was no association between DCEcM1 and baseline paretic upper limb ARAT, FM or PD score (all R2 < 0.09, P > 0.4).

Table 2 Neurophysiological, clinical and grip-lift measures at baseline. Paretic Neurophysiological MEP amplitude (mV) SAI (%) Sensorya Pain (a.u.) Spatial acuity (mm) Cutaneous sensory threshold (g)

Grip-lift kinetics Preload duration (ms) Preload force (N) UL function ARAT (median score [range]) a b

Index Thumb Index Thumb

Nonparetic

t11

P

0.55 ± 0.24 3.55 ± 2.61

2.33 ± 0.41 20.62 ± 6.24

3.41 3.13

0.003 0.007

10.5 ± 0.96 3.17 ± 0.19 3.55 ± 0.16 0.47 ± 0.12 0.50 ± 0.12

8.8 ± 0.82 2.88 ± 0.28 3.17 ± 0.23 0.36 ± 0.08 0.43 ± 0.07

1.81 0.80 1.20 1.18 0.63

0.101 0.442 0.257 0.266 0.544

515 ± 117 1.36 ± 0.44

219 ± 59 0.46 ± 0.21

2.11 1.89

0.024 0.043

3.06

P 0.002

Z 38 [6–57]

57 [43b–57]

One patient was unable to follow the instructions for sensory testing secondary to language difficulties. One patient had a longstanding arthritic condition affecting both hands.

Please cite this article in press as: Ackerley SJ et al. Priming sensorimotor cortex to enhance task-specific training after subcortical stroke. Clin Neurophysiol (2013), http://dx.doi.org/10.1016/j.clinph.2013.11.020

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Table 3 Stimulation and training measures at baseline. Paretic

Stimulation parameters Stimulation intensity (50%MEPmax) Perceptual threshold (mA) Rest motor thresholda (%) Active motor thresholdb (%) TBS stimulation intensity (90%AMT) Training No. of pegs a b c

Nonparetic

iTBS

cTBS

Sham

Mean

iTBS

79.5 ± 3.8

79.3 ± 3.6

79.4 ± 3.3

79.4 ± 3.5

63.0 ± 3.4

172 ± 72

178 ± 67

Between Interaction PROTOCOLS

Sham

Mean

F1,11

P

61.8 ± 2.8

63.3 ± 2.4

62.7 ± 2.8

12.47

0.005 0.438 0.651 0.239 0.789

1.14 ± 0.13 43.8 ± 3.0 57.1 ± 2.2 48.8c ± 2.3

1.11 ± 0.14 44.3 ± 1.9 57.8 ± 1.9 50.6 ± 2.0

1.10 ± 0.11 0.382 0.549 0.137 0.873 0.187 0.831 44.7 ± 2.4 18.25 0.000 0.191 0.828 1.820 0.186 57.8 ± 2.0 0.416 0.665 50.6 ± 1.8 1.465 0.253

cTBS

1.05 ± 0.12 1.06 ± 0.09 1.09 ± 0.13 1.06 ± 0.09 1.06 ± 0.12 66.2 ± 5.9 65.3 ± 5.2 68.5 ± 5.0 67.3 ± 5.5 46.2 ± 2.7 58.4 ± 2.3 52.8 ± 2.1

189 ± 74

Between HANDS

180 ± 71

F2,22

P

F2,22

P

0.634 0.540

RMT collected with a monophasic Magstim 200. MT collected with a biphasic RapidStim. Three participants were stimulated at below 90% AMT (2 at 70%, 1 at 80% AMT) as visible activity of the nonparetic hand was observed.

Fig. 2. (A) Change in paretic FDI short latency afferent inhibition (DSAI, %). Positive values indicate increased inhibition. Gray background shading indicates after training commenced. Bars indicate time (POST5, POST29, POST48). (B) Paretic FDI MEP amplitude (%PRE) immediately after TBS (POST5), after movement (POST18) (light gray background shading), and during (POST29) and after training (POST48) (darker gray background shading). (C/D) Regression analysis between DCEiM1 (%) immediately after iTBSiM1 (POST5) (C) and DCEcM1 (%) immediately after cTBScM1 (POST5) (D) (positive values indicate facilitation, negative values indicate suppression) and NIHSS (lower values indicate less overall stroke severity). Black bars and symbols indicate iTBSiM1; gray, cTBScM1; and white, sham TBS. For figures (C) and (D), data points are participants. Error bars are SEM. P < 0.05. # differs from baseline, P < 0.05.

Further regression analysis was conducted to explore whether grip performance improvement (%PD at POST35) was

related to DSAI (%) at POST29. There was no association (R2 < 0.06, P > 0.5).

Please cite this article in press as: Ackerley SJ et al. Priming sensorimotor cortex to enhance task-specific training after subcortical stroke. Clin Neurophysiol (2013), http://dx.doi.org/10.1016/j.clinph.2013.11.020

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4. Discussion This study investigated the sensorimotor consequences of M1 TBS in patients at the chronic stage after subcortical stroke. After iTBSiM1 there was evidence of increased SAI during training that did not occur after cTBScM1. The increase in SAI was accompanied by increased MEP amplitude indicative of greater corticomotor excitability after iTBSiM1. The increase in SAI in the paretic FDI indicates that iTBSiM1 may have increased the responsiveness of ipsilesional M1 to afferent input. Both real TBS protocols combined with task-specific training led to improved grip-lift kinetics, as found previously (Ackerley et al., 2010). Therefore, enhanced SAI may not be necessary for improved grip performance. Ipsilesional SAI increased after iTBSiM1. It seems unlikely that this was due to increased ipsilesional S1 excitability for several reasons. First, the stimulation intensity used for M1 TBS was lower than that used with non-patterned rTMS in previous studies (Enomoto et al., 2001; Tsuji and Rothwell 2002) so that any direct facilitation of S1 from M1 stimulation would be minimal (Ishikawa et al., 2007). However, it is acknowledged that Nakatani-Enomoto et al. (2012) showed potentiation of somatosensory evoked potential after facilitatory quadripulse transcranial magnetic stimulation at 90% AMT. Second, SAI did not increase immediately after iTBSiM1, but increased during subsequent training. This delayed effect argues against direct excitation of S1 that would result in an immediate increase in SAI. Third, there were no effects on sensory performance. The thresholds for spatial acuity, cutaneous sensory threshold and pain were unchanged at all time-points indicating that enhanced early sensory processing is unlikely to account for the observed increase in SAI. A possible limitation of the study is that the TMS stimulus intensity was not adjusted after TBS to maintain a stable non-conditioned MEP amplitude. This may have influenced the SAI measures. However, NC MEP amplitude was maintained in a range allowing accurate interpretation of SAI (Udupa et al. 2009). Furthermore, SAI was maximally increased 29 min after iTBS (POST29), and test MEP amplitude had returned to baseline at this time (Fig. 2). After iTBSiM1, there was an immediate increase in ipsilesional corticomotor excitability and enhanced grip performance with the paretic hand, as reported previously (Ackerley et al., 2010). Intermittent TBS may have facilitated synaptic efficacy within ipsilesional M1 (Huang et al., 2007; Ziemann and Siebner, 2008) and contributed to improved paretic grip precision. Given that iTBSiM1 facilitated M1 excitability, it is possible that enhanced SAI resulted from an increase in the responsiveness of M1 to task-related input from S1 and that this contributed to more efficient sensorimotor integration during training. However there was no association between change in grip lift performance and ipsilesional SAI. There was also a reduction in contralesional M1 excitability after iTBSiM1 consistent with earlier studies of healthy adults (Suppa et al., 2008) and acute stroke patients (Di Lazzaro et al., 2008, 2010). This study lends support to the interhemispheric competition model whereby ipsilesional M1 function may be hampered by contralesional M1 hyperexcitability following stroke (Nowak et al., 2009). The after-effects of cTBScM1 on corticomotor excitability varied across individuals. There was no immediate suppression of contralesional M1 excitability consistent with an earlier study (Ackerley et al., 2010). Post hoc regression analyses indicated this was probably due to inter-individual differences. Patients with the lowest NIHSS scores (less severe stroke) showed the greatest nonparetic FDI MEP suppression after cTBScM1, whereas patients with higher NIHSS scores tended to exhibit contralesional M1 facilitation after cTBScM1. In contrast there was no relationship between stroke severity and ipsilesional M1 facilitation after iTBSiM1.

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Contralesional M1 may be recruited to a greater extent in more severely affected patients (Ward et al., 2006; Lotze et al., 2006, 2011; Stinear et al., 2007; Bradnam et al., 2011). Under these conditions a homeostatic response to suppressive stimulation of the contralesional M1 may be biased towards facilitation. After cTBScM1, ipsilesional M1 excitability increased once training commenced in parallel with improvements in grip-lift performance of the paretic hand. It is plausible that an interaction with training is required to observe consistent increases in ipsilesional M1 excitability after cTBScM1, although this has not been borne out in previous studies (Di Lazzaro et al., 2008; Ackerley et al., 2010). It is possible that factors that contribute to heterogeneity between participants after stroke (such as lesion location, chronicity and hemisphere affected) along with those that contribute to variability in response to cTBS (such as voluntary activation associated with limb movements, and BDNF genotype) may contribute to variation in effects observed after cTBS (Martin et al., 2006; Cheeran et al. 2008; Gentner et al., 2008). There were no effects of TBS on paretic upper limb function. We previously reported an association between suppression of ipsilesional corticomotor excitability and deterioration of paretic upper limb function after cTBScM1 (Ackerley et al., 2010). Patients with residual functional integrity of ipsilesional CST, as indicated by the presence of MEPs in the paretic FDI, were recruited in the present study to minimise the likelihood of temporary reduction in paretic arm function. Training primed by cTBScM1 did not suppress paretic FDI MEPs and did not have a detrimental effect on ARAT score. It may be that patients with MEPs are more likely to benefit from cTBScM1 than those without, as the latter may be compensating with contralesional motor areas to a greater extent. A cautious approach to protocols aimed at suppression of contralesional M1 is warranted (Ackerley et al., 2010). In summary, iTBSiM1 and cTBScM1 enabled patients with subcortical stroke to engage in better quality sensorimotor training. Continuous TBScM1 did not alter sensorimotor integration as measured by short-latency afferent inhibition, and its effects on corticomotor excitability were related to stroke severity and less consistent than those produced by iTBSiM1. Conversely, intermittent TBSiM1 increased the receptiveness of ipsilesional M1 to afferent input produced during paretic upper limb sensorimotor training. This is a useful reminder that the effects of iTBS on M1 may not be limited to modulation of its output, but can also alter its receptiveness to input. Overall, priming training with iTBSiM1 produced more predictable and beneficial sensorimotor after-effects. Funding This work was supported by a W & B Miller scholarship from the Neurological Foundation of New Zealand (to S.J.A). Acknowledgements The authors would like to thank Fred Noten, Linda O’Connor and Mairi Liggins, Professor Ngaire Kerse, Dr. Daniel Exeter for assistance with data collection. References Ackerley SJ, Stinear CM, Barber PA, Byblow WD. Combining theta burst stimulation with training after subcortical stroke. Stroke 2010;41:1568–72. Bara-Jimenez W, Shelton P, Hallett M. Spatial discrimination is abnormal in focal hand dystonia. Neurology 2000;55:1869–73. Bell-Krotoski J, Tomancik E. The repeatability of testing with Semmes-Weinstein monofilaments. J Hand Surg Am 1987;12:155–61. Blennerhassett M, Matyas T, Carey L. Impaired discrimination of surface friction contributes to pinch grip deficit after stroke. Neurorehabil Neural Repair 2007;21:263–72.

Please cite this article in press as: Ackerley SJ et al. Priming sensorimotor cortex to enhance task-specific training after subcortical stroke. Clin Neurophysiol (2013), http://dx.doi.org/10.1016/j.clinph.2013.11.020

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Please cite this article in press as: Ackerley SJ et al. Priming sensorimotor cortex to enhance task-specific training after subcortical stroke. Clin Neurophysiol (2013), http://dx.doi.org/10.1016/j.clinph.2013.11.020

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