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Bilateral Priming Before Wii-based Movement Therapy Enhances Upper Limb Rehabilitation and Its Retention After Stroke: A Case-Controlled Study Christine T. Shiner, Winston D. Byblow and Penelope A. McNulty Neurorehabil Neural Repair published online 13 March 2014 DOI: 10.1177/1545968314523679 The online version of this article can be found at: http://nnr.sagepub.com/content/early/2014/03/12/1545968314523679

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research-article2014

NNRXXX10.1177/1545968314523679Neurorehabilitation and Neural RepairShiner et al

Article

Bilateral Priming Before Wii-based Movement Therapy Enhances Upper Limb Rehabilitation and Its Retention After Stroke: A Case-Controlled Study

Neurorehabilitation and Neural Repair 1­–11 © The Author(s) 2014 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1545968314523679 nnr.sagepub.com

Christine T. Shiner1, Winston D. Byblow, PhD2, and Penelope A. McNulty, PhD1

Abstract Background. Motor deficits after a stroke are thought to be compounded by the development of asymmetric interhemispheric inhibition. Bilateral priming was developed to rebalance this asymmetry and thus improve therapy efficacy. Objective. This study investigated the effect of bilateral priming before Wii-based Movement Therapy to improve rehabilitation after stroke. Methods. Ten patients who had suffered a stroke (age, 23-77 years; 3-123 months after stroke) underwent a 14-day program of Wii-based Movement Therapy for upper limb rehabilitation. Formal Wii-based Movement Therapy sessions were immediately preceded by 15 minutes of bilateral priming, whereby active flexion-extension of the less affected wrist drove mirror-symmetric passive movements of the more affected wrist through a custom device. Functional movement was assessed at weeks 0 (before therapy), 3 (after therapy), and 28 (follow-up) using the Wolf Motor Function Test (WMFT), upper limb Fugl-Meyer Assessment (FMA), upper limb range of motion, and Motor Activity Log (MAL). Casematched controls were patients who had suffered a stroke who received Wii-based Movement Therapy but not bilateral priming. Results. Upper limb functional ability improved for both groups on all measures tested. Posttherapy improvement on the FMA for primed patients was twice that of the unprimed patients (37.3% vs 14.6%, respectively) and was significantly better maintained at 28 weeks (P = .02). Improvements on the WMFT and MAL were similar for both groups, but the pattern of change in range of motion was strikingly different. Conclusions. Bilateral priming before Wii-based Movement Therapy led to a greater magnitude and retention of improvement compared to control, especially measured with the FMA. These data suggest that bilateral priming can enhance the efficacy of Wii-based Movement Therapy, particularly for patients with low motor function after a stroke. Keywords rehabilitation, cortical excitability, interhemispheric inhibition, upper limb, brain priming Brain priming has emerged as a strategy to improve the efficacy and retention of rehabilitation after stroke and help reduce the global disease burden of stroke. The aim of priming is to enhance the brain’s responsiveness to motor rehabilitation by modulating cortical excitability to create a more neuroplastic environment prior to therapy.1-5 Priming may be used to rebalance the asymmetry in inhibition known to develop between the hemispheres after stroke.1-3 This inhibitory imbalance reduces the excitability of the lesioned motor cortex,1 further reducing motor output and limiting functional movement and the potential for motor recovery.3,6,7 Therefore, rebalancing interhemispheric excitability to prime the brain after a stroke and improve rehabilitation outcomes is a developing clinical construct. 4,5,7-11 Bilateral priming with repetitive, mirror-symmetric active-passive movements (active-passive bilateral priming [APBP]) is a novel priming approach in which a peripheral movement paradigm circumvents many of the limitations of

more conventional priming strategies.4,5,12-14 A custom device facilitates rhythmic, bimanual flexion-extension movements of the wrists in which mechanical coupling enables active flexion and extension of the less affected wrist to drive the passive, more affected wrist. Active-passive movements have been shown to modulate corticomotor excitability when performed specifically in a mirror-symmetric manner.12,14,15 Brief bilateral priming sessions can (1) increase excitability in the resting, ipsilesional hemisphere; (2) increase transcallosal 1

Neuroscience Research Australia and the University of New South Wales, Sydney, Australia 2 Centre for Brain Research, The University of Auckland, Auckland, New Zealand Corresponding Author: Penelope A. McNulty, PhD, Neuroscience Research Australia, Barker Street, Randwick, NSW 2031, Australia Email: [email protected]

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Table 1.  Patient Demographics. Patient 1 2 3 4 5 6 7 8 9 10

Age, y

Sex

Time after stroke, mo

Stroke type

More affected side

Dominant side

Pretherapy WMFT time,a s

Pretherapy FMA scoreb

75 23 62 60 77 74 64 68 71 72

M F M F F M M M F M

10 13 123 24 34 7 24 19 108 4

Hemorrhagic Hemorrhagic Ischemic Hemorrhagic Ischemic Hemorrhagic Ischemic Hemorrhagic Hemorrhagic Ischemic

L R R L L R R L R R

R R R L R R R L R R

3.2 74.4 8.1 105.2 120.0 12.1 97.3 67.5 4.1 82.8

59 42 54 18 5 48 20 46 61 19

F, female; L, left; M, male; R, right. a. Wolf Motor Function Test (WMFT) mean time for 15 timed tasks (maximum possible time of 120 seconds per task). b. Fugl-Meyer Assessment (FMA) upper limb motor subscale (maximum score of 66).

inhibition from the ipsilesional (passive) to the contralesional (active) hemisphere; and (3) increase intracortical inhibition in the contralesional hemisphere.4,12 These changes outlasted the priming session, were shown to accelerate motor learning in a healthy cohort,14 and contributed to rebalancing interhemispheric excitability after stroke that was associated with improved performance in subsequent motor therapy and increased retention of therapy benefits.4 Few studies have trialed APBP in a population after stroke. Since the feasibility of this technique was first established after stroke in 2004,12 only three studies have investigated the use of this active-passive movement paradigm as a brain-priming strategy before stroke therapy: one with self-directed therapy;4 and a pilot study,13 and a randomized control trial5 in conjunction with standard in-patient physical and occupational therapy. The present study extends this work into a chronic patient cohort undertaking a highly structured rehabilitation program without the confounding of concurrent rehabilitation strategies. Here, we assessed the efficacy of APBP as an adjuvant priming modality to Wii-based Movement Therapy16 after stroke. We hypothesized that the combined therapy protocol would be well tolerated by patients after a stroke and that those who underwent bilateral priming before Wii-based Movement Therapy would have greater functional improvement immediately after therapy and better retention at 6 months than a case-matched cohort of patients who had suffered a stroke who received Wii-based Movement Therapy alone.

Methods Participants Ten community-dwelling patients who had suffered a stroke were consecutively recruited (Table 1), with a mean ± standard deviation age of 64.6 ± 15.7 years and 36.6 ± 42.8

months after a stroke. Patients were recruited from Prince of Wales and St Vincent’s Hospitals, Sydney, and all were hemiparetic with an upper limb deficit following a unilateral stroke. Inclusion criteria included ≥3 months after a stroke, stable blood pressure, able to communicate in English, and cognitive competency assessed as a MiniMental State Examination score ≥24. Exclusion criteria included receptive aphasia, comorbidities affecting upper limb sensorimotor function, and participation in other formal rehabilitation programs. All patients gave informed, written consent, and the study was approved by the Human Research Ethics Committee, St Vincent’s Hospital, and conducted in accordance with the Declaration of Helsinki. Each patient was case matched to an unprimed control patient from an historic cohort who received the same standardized protocol of Wii-based Movement Therapy but without bilateral priming. A weighted, hierarchical algorithm was developed to identify the most appropriate case match for each patient based on assessments of pretherapy functional ability and demographic information (Table 2). Each item in the algorithm was scored for the match between the primed patient and the candidate case match. The weighting assigned to each parameter reflected its perceived importance to case matching. To verify the accuracy of this algorithm, each primed patient was scored against 4 potential unprimed case matches by 8 blinded assessors. The case match with the highest overall score was identified as the most appropriate unprimed control. Case-matching results are summarized in Table 3. There were no significant differences between primed and unprimed groups for any parameter at baseline. Motor functional assessments were performed at week 0 (immediately before therapy), week 3 (immediately after the 14-day protocol), and week 28 (6-month follow-up). Patients’ upper limb functional ability was assessed using the upper limb motor Fugl-Meyer Assessment17 (FMA) and the Wolf Motor Function Test18 (WMFT). The Motor

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Shiner et al Table 2.  Criteria and Scoring System Used for Case Matching. Case-matching criteria

Score

Functional status   WMFT timed tasks, mean time   Upper limb FMA score   MAL-QOM score Demographics   Months after stroke   Dominant vs nondominant hemiparesis   Stroke type (ischemic vs hemorrhagic)  Age  Sex Maximum possible score

  0-3 0-3 0-3   0-3 0-3 0-2 0-2 0-1 21

Each primed patient was compared to 4 potential control patients (from a total pool of 28) using the functional and demographic criteria outlined. A score was assigned to each parameter, indicating how closely the primed patient matched a given control, with weighting assigned so that the maximum possible score for each component reflected its perceived importance to case matching. For each potential match, component scores were added to give a total case-matching score out of 21. The control patient with the highest total score was selected as the most appropriate case match. FMA, Fugl-Meyer Assessment; MALQOM, Motor Activity Log Quality of Movement subscale; WMFT, Wolf Motor Function Test.

Table 3.  Comparison of Mean Demographics of Primed and Case-Matched Control Cohorts. Primed patients Age, y Sex, n  Male  Female   Time after stroke, mo Etiology, n  Ischemic  Hemorrhagic Hand dominance, n   Dominant more affected   Nondominant more affected Pretherapy WMFT time,a s Pretherapy FMA scoreb Pretherapy MAL-QOM scorec

64.6 (23-77) 6 4 36.6 (4-123) 4 6 8 2 57.6 (3.2-120) 37.2 (5-61) 49.5 (0-133)

Case-matched controls 60.5 (22-74)   6 4 20.3 (5-46)   5 5   5 5 56.1 (3.2-120) 36.8 (4-61) 51.2 (0-134)

Data are presented as mean (range) unless otherwise specified. APBP, activepassive bilateral priming. a. Wolf Motor Function Test (WMFT) mean time for 15 timed tasks (maximum possible time of 120 seconds per task). b. Fugl-Meyer Assessment (FMA) upper limb motor subscale (maximum score of 66). c. Total score for 30 items of the Motor Activity Log Quality of Movement subscale (MAL-QOM) (maximum score of 150). There were no significant differences between groups for any parameter.

Activity Log Quality of Movement subscale19 (MALQOM) was used as an index of the transfer of therapyinduced improvements to the performance of unrelated activities of daily living.

Active and passive ranges of motion at the shoulder, elbow, wrist, and digits I and II were assessed using a handheld goniometer.20 Spasticity of the shoulder, elbow, and wrist was assessed using the Tardieu Scale.21 Lower limb function was assessed using the Berg Balance Scale22 and 6-minute walk test.23,24 Patient satisfaction and self-perceived functional improvement were rated on a 10-point visual analog scale during posttherapy assessments. The Box and Block Test25 (BBT) of gross manual dexterity was used before therapy to stratify patients according to upper limb motor function. Patients capable of picking up and moving >1 block before therapy were classifed as having high motor function, and those unable to pick up or move blocks were classified as having low motor function.26

Therapy Protocol Patients completed an intensive 14-day combined protocol of bilateral priming prior to the standardized Wii-based Movement Therapy program, which specifically targeted the more affected upper limb (Figure 1). Formal sessions were guided by a therapist, while home practice was selfdirected and when necessary supervised by a carer. Bilateral priming. Each formal therapy session began with 15 minutes of bilateral priming using a customized table-mounted device. Patients were seated with elbows flexed, forearms semipronated, and both hands secured to the adjustable hand pieces (Figure 1). They were instructed to perform rhythmic, voluntary flexion and extension of the less affected wrist and allow the more affected wrist to be passively driven through mirror-symmetric movements via a mechanical linkage that confers an inertial advantage.4 Patients were instructed to focus on the active, less affected wrist, keeping the more affected side relaxed. The number of wrist flexion-extension cycles in each session was recorded, and patients were encouraged to increase the number of movements per session. Wii-based Movement Therapy.  The intensive 14-day protocol was that developed by Mouawad and colleagues.16 Patients completed 60 minutes of formal, supervised therapy on 10 consecutive weekdays, immediately after bilateral priming. Home training commenced on day 2 of the program and progressively increased from 15 to 180 minutes per day depending on progress and motor ability. Nintendo Wii and Wii Sports (Nintendo, Kyoto, Japan) were used as an upper limb rehabilitation tool. Depending on individual deficits and functional progress, different games were introduced and varied to tailor rehabilitation to each patient’s needs. Progress was monitored daily via a motor activity diary, completion of the MAL-QOM, and patientcentered problem solving and goal setting.

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Data Analysis Data that were normally distributed were analyzed using repeated-measures 2-way analyses of variance (ANOVAs) with factors of group (primed, unprimed) and time (week 0, 3, 28) and post hoc Holm-Sidak analyses for multiple pairwise comparisons. Data that were not normally distributed were analyzed using a 1-way ANOVA on ranks with a post hoc Tukey test for multiple pairwise comparisons. Normally distributed data are presented as mean ± standard error of the mean, and data that were not normally distributed are presented as median and interquartile range (IQR). Differences were considered significant when P < .05.

Results The primed Wii-based Movement Therapy protocol was well tolerated and successfully completed by all 10 patients. The 6 patients who could not move any BBT blocks with their more affected hand before therapy were classified as having low motor function. The remaining 4 patients with high motor function moved a mean of 41 blocks (range, 29-51) with the more affected hand. Due to an unrelated medical condition, 1 patient from the primed group was unable to complete week-28 follow-up assessments. For this reason, follow-up data are reported for the 9 remaining primed patients and 9 unprimed case matches.

FMA There was a main effect of time on FMA upper limb motor scores for all patients. The FMA scores improved from 37.2 ± 6.3 to 43.7 ± 5.6 for the primed cohort (F2,17 = 16.8, P = .002) and from 36.8 ± 7.4 to 40.0 ± 7.3 (F2,17 = 5.238, P = .008) for the unprimed cohort at week 3 (Figure 2D). When normalized to pretherapy values, the increased FMA scores for the primed cohort of 37.3% ± 12.8% were more than twice those of the unprimed group of 14.6% ± 7.0%. Despite this, post hoc analyses revealed no difference between the primed and unprimed groups immediately after therapy (P = .08). At week 28, there was an interaction between group and time for the FMA, with primed patients making greater improvements than unprimed patients (F2,32 = 4.3, P = .02). Primed patients demonstrated additional improvement at week 28 with a mean score of 48.9 ± 4.7 (F2,17 = 16.8, P = .02), whereas unprimed patients scored 42.2 ± 8.1, maintaining but not extending the immediate posttherapy gains. The FMA data from each upper extremity subsection (A: shoulder, elbow, forearm; B: wrist; C: hand; D: coordination, speed) were examined independently. There was a group by time interaction for the coordination and speed section (F2,34 = 3.5, P = .04), with primed patients improving

from 2.1 ± 0.5 to 3.1 ± 0.6 at week 3 and unprimed patients remaining unchanged (2.3 ± 0.7 at week 0 and 2.4 ± 0.7 at week 3). There were no other subsection interactions between group and time.

WMFT The 2 WMFT strength-based assessments showed no significant differences with time or group, and therefore, the WMFT data hereafter refer only to the 15 timed tasks. The mean WMFT time for the primed patients revealed a nonsignificant trend toward improvement at week 3, decreasing from 57.6 ± 14.6 seconds to 53.1 ± 14.7 seconds (P = .059) (Figure 2F). At week 28, there was additional improvement for the primed patients, with the WMFT mean time further reduced to 40.8 ± 13.5 seconds (F2,17 = 5.5, P = .015). The WMFT mean time also improved for the unprimed patients at week 3, decreasing from 56.1 ± 15.1 seconds to 53.0 ± 14.3 seconds, but not significantly. At week 28, the mean time taken by unprimed patients to complete the WMFT timed tasks was further reduced to 48.7 ± 15.1 seconds (F2,17 = 8.2, P = .003). There was no interaction between group and time for the WMFT (P > .1).

Use of the Hand in Everyday Activities There was a main effect of time on the MAL-QOM (P < .001), indicating that both groups made significant improvements in the use of the more affected upper limb in activities of daily living. Median MAL-QOM scores at week 3 increased from 44 (IQR, 8.8-68.5) to 69 (IQR, 27.3-109) for the primed cohort (H(2) = 13.6, P < .001) and from 41 (IQR, 4.5-79.3) to 66 (IQR, 27.5-114.25) for the unprimed group (H(2) = 11.6, P = .001). These improvements were sustained without differences by both primed and unprimed groups at week 28, scoring 69 (IQR, 26-131) and 61 (IQR, 50-117), respectively. There was no effect of group on MAL-QOM scores.

Range of Motion Passive and active ranges of motion increased at all joints for primed patients (Figure 3). Improvements were seen at week 3 for passive measures at digit I of 6.25° ± 2.5° (F2,36 = 6.4, P = .04) and active measures at digit I of 12.1° ± 4.3° (F2,36 = 6.4, P = .004) and digit II of 13.0° ± 4.9° (F2,36 = 4.3, P = .02), but not at the shoulder and elbow. The pattern of improvements in the unprimed group was different. Passive range of motion increased by 9.2° ± 4.8° at digit II (F2,34 = 3.8, P = .03), with no changes in active range of motion, although there was a nonsignificant trend for increased shoulder movement of 4.5° ± 2.4° (P = .07). At week 28, primed patients maintained their gains in distal active range

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Shiner et al pre post

pre-therapy assessments (week-0) APBP + formal WMT WMT home training post-therapy assessments (week-3)

Wii Fitness

Guest C Balance

Speed

Stamina

Wii Fitness Age: 20 30 40 50 60 70 80

60

MAY

APR

Done SO N Y

Wii

A

hours

1 2

post

pre 1 2 3 4 5 6 7 8 9 10 11 12 13 14 days

Figure 1.  Combined active-passive bilateral priming (APBP) and Wii-based Movement Therapy (WMT) protocol. During the 14-day protocol, patients participated in 10 formal therapy sessions (filled symbols). These commenced with 15 minutes of bilateral priming, which was delivered via a custom table-mounted device (left) in which patients performed rhythmic flexion-extension movements of their less affected wrist to drive their passive, more affected wrist through mirror-symmetric movements. Priming was immediately followed by 1 hour of formal Wii-based Movement Therapy. Home practice consisting of Wii-based Movement Therapy activities began on day 2 of the program (open symbols) and progressively increased in duration. Functional assessments were conducted before (week 0), immediately after (week 3), and 6 months after (week 28) the intervention period. Patient progress was monitored daily throughout the 14-day protocol.

of motion in addition to making improvements at the shoulder of 11.6° ± 3.5° (F2,55 = 9.0, P < .001) and at the elbow of 19.5° ± 7.3° (F2,17 = 5.3, P = .017). There were no changes in range of motion for the unprimed patients at week 28.

Spasticity There were no between-group differences for pretherapy Tardieu Scale scores of shoulder, elbow, and wrist spasticity or between joints (mean, 1.8 ± 0.3 primed patients and 2.2 ± 0.3 unprimed patients). Neither the primed nor unprimed group had any change in upper limb spasticity at week 3 or week 28.

Lower Limb Measures For both balance and walking, there was a main effect of time but not of group. Berg Balance Scale scores at week 3 were increased from 42.2 ± 4.3 to 45.1 ± 3.3 for primed patients (F2,17 = 3.5, P = .02) and from 44.9 ± 4.3 to 47.8 ± 3.5 for unprimed patients (F2,17 = 6.3, P = .02). Improvements were maintained at week 28, with primed and unprimed patients scoring 48.5 ± 2.3 and 47.7 ± 3.8, respectively. The mean distance of the 6-minute walk test increased for the primed patients from 340.2 ± 56.2 m to 375.4 ± 63.2 m at week 3 and increased further to 401 ± 60.1 m at week 28 (F2,17 = 3.7, P = .045). Similarly, the unprimed patients’ mean distance increased from 305.3 ± 59.2 m to 338.3 ± 63.5 m at week 3 and further improved to 346.0 ± 61.8 m at week 28 (F2,17 = 4.7, P = .027). There were no betweengroup differences on measures of lower limb performance.

Priming Repetitions The number of wrist flexion-extension cycles completed in the first priming session varied between patients from 113 to 962. Regardless of the initial count, all patients increased by a mean of 101.0% ± 20.3%. In session 1, the mean was 626.5 ± 96.47 repetitions, which increased to 1156.4 ± 175.96 by session 10 (P < .001). There was no correlation between the number of priming repetitions and patient improvement on the FMA, the most sensitive measure of functional ability. Similarly, patient improvements on the FMA, WMFT, and MAL did not correlate with (1) age, (2) time after stroke, or (3) lesion location for either the primed or unprimed group.

Satisfaction and Improvement Regardless of age and level of impairment, all patients reported high satisfaction with the combined therapy protocol. The mean satisfaction score for the primed patients was 9.0 ± 0.4, and their self-perceived improvement was rated 6.9 ± 0.6. The scores for the unprimed group were 8.7 ± 0.4 and 6.8 ± 0.5, respectively.

Discussion This is the first study to combine bilateral priming with a comprehensive structured therapy protocol in the chronic phase after a stroke. The dual therapy of bilateral priming and Wii-based Movement Therapy was well tolerated and improved functional movement ability for all patients. This

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BBT blocks moved

A

stratification - primed

B

stratification - unprimed

60 40 20 0

0

20

40

60

80 100 120

0

WMFT mean time (s)

C

baseline (week-0)

D

60

80 100 120

change

16

50 40

Δ FMA

pre FMA score

40

20

60

30

12 8

20 4

10

0

0

F

120

72 48 24 0

10 0

96

Δ WMFT (s)

pre WMFT mean time (s)

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WMFT mean time (s)

70

E

primed low primed high unprimed low unprimed high

-10 -20 -30

primed

unprimed

-40

week-3 week-28

week-3 week-28

primed

unprimed

Figure 2.  Improvements in functional movement ability. All panels contain individual patient data, with mean (solid line) and standard errors (dashed line). Primed (filled) and unprimed (open) patients with low upper limb motor function are denoted by circles, and those with high motor function are denoted by diamonds. (A, B) Pretherapy Box and Block Test (BBT) scores plotted against pretherapy Wolf Motor Function Test (WMFT) mean time for primed (A) and unprimed (B) groups. There was a bimodal distribution of functional ability in both groups used to stratify patients with high or low motor function. (C) Total upper limb Fugl-Meyer Assessment (FMA) scores at week 0 for primed and unprimed patients. Maximum possible score of 66 indicated by dashed line. (D) Change in FMA scores at week 3 and week 28. Primed patients had significantly greater changes than unprimed patients at week 28 (P = .02). (E) Mean time per task at week 0 for 15 timed tasks of the WMFT for primed and unprimed patients. Maximum time allowed per task (120 seconds) indicated by dashed line. A lower time indicates better function, F. Change in mean time per WMFT task at week 3 and week 28. Pretherapy completion time indicated by dashed line. A reduction in time represents an improvement.

was despite the heterogeneity of the cohort, ranging from very low to high motor function before therapy; the extent of chronicity after stroke (up to 123 months); and the prior

completion of in- and out-patient therapy. While the sample size of this study is small, its demographic and functional diversity (Table 1) reflect the broad spectrum of

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Shiner et al

25

B

primed

25

20

20

15

15

Δ degrees

Δ degrees

A

10

10

5

5

0

0

-5

week-3 week-28

unprimed

-5 shoulder elbow wrist

dig I

dig II

shoulder elbow

wrist

dig I

dig II

Figure 3.  Changes in range of motion. Pooled patient data, with mean changes in active range of motion at each site tested and standard errors. (A) Change in active range of motion for primed patients (filled symbols). The solid line indicates change at week 3, and the dashed line indicates change at week 28. Primed patients had significant gains at digit I (P = .004) and digit II (P = .02) at both time points, in addition to improvements at the shoulder (P < .001) and elbow (P = .017) at week 28. (B) Change in active range of motion for unprimed patients (open symbols). Again, the solid line indicates change at week 3, and the dashed line indicates change at week 28.

impairments after stroke. In this study, patients who received bilateral priming before Wii-based Movement Therapy had a significantly greater functional improvement on the FMA than unprimed patients from an historic cohort who received Wii-based Movement Therapy alone. This extends previous findings4 and suggests that bilateral priming can increase the efficacy of Wii-based Movement Therapy, particularly for patients with low motor function after a stroke. APBP modulates inhibitory pathways both within and between hemispheres in healthy patients and after stroke.4,5,12,14 There is growing evidence to suggest that these inhibitory changes occur via GABAergic pathways in the cortex,14,15 and it is hypothesized that priming promotes plasticity in the lesioned hemisphere via down-regulation of GABAergic inhibition.4,5,14,15 In the present study, bilateral priming may have enhanced the efficacy of Wii-based Movement Therapy by creating a cortical environment more conducive to therapy-induced plasticity.

Functional Status and Its Impact on Rehabilitation The exclusion criteria for this study were deliberately minimal to capture patients who may otherwise not receive upper limb rehabilitation due to their functional impairment. Wii-based Movement Therapy provides a unique opportunity for patients with low motor function to receive rehabilitation.27 While the efficacy of more conventional strategies such as constraint-induced movement therapy is

well documented,28-30 safety concerns31,32 and stringent selection crtieria29 may render them less suitable for patients with low motor function. The present results demonstrate that with appropriate rehabilitation, even patients with extremely low motor function are capable of substantial improvement and should be targeted for rehabilitation.. This study was the first to investigate the effect of bilateral priming in patients with low and very low motor function after stroke. The 6 patients with low motor function in the present study were unable to move any BBT blocks before therapy and could not have performed the block manipulation tasks previously used for bilaterally primed self-directed therapy.4 When stratified according to motor function, the FMA and WMFT results of the present study suggest that these patients may benefit the most from APBP and Wii-based Movement Therapy (Figure 2). Given the challenge of identifying suitable and effective rehabilitation strategies for patients with low motor function after stroke,33,34 these results suggest that further investigation of adjunctive bilateral priming is warranted. The quantitative assessment of motor ability and its improvement in patients with low motor function is challenging. The FMA was the most sensitive measure in this study comprised of patients with predominantly low motor function. This replicates previous findings, which suggest that the FMA may be a more salient assessment for patients after stroke with low motor function than the WMFT.27,35,36 Despite a comprehensive suite of functional assessments including the FMA, it was evident that no single test adequately captured the diversity of improvements made by

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patients with extremely low motor function. The 6 patients with low motor function in the current study perceived their improvement as equivalent to that of the pooled unprimed group (6.2 ± 0.8 vs 6.8 ± 0.5, respectively). This suggests that the improvements of those with low motor function were functionally relevant, even when such changes may not have reached statistical significance or the minimal clinically important difference.

Differences Between Primed and Control Groups When FMA data for each upper extremity subsection were examined independently, a significant effect of priming was observed for the coordination and speed subsection only. It is possible that the rhythmic, bilateral nature of priming movements contributed to greater improvements in coordination for the primed group. However, this effect has not been seen previously4,5,13 and requires further investigation. The patterns of improved active range of motion for primed and unprimed patients at week 3 were strikingly different (Figure 3). The most prominent improvements for primed patients occurred distally at the digits, while unprimed patients showed greater changes in the more proximal elbow and shoulder joints. Bilateral priming may focus therapy-induced improvement to distal muscles by preferentially modulating inhibition in cortical areas that supply the muscles directly engaged in the priming movements of wrist flexion-extension. Passive stretching of the muscles crossing the wrist during priming may also have contributed to these differences by altering muscle tone. The different proximal-to-distal patterns of improvement for the primed and unprimed groups were less divergent at week 28. Primed patients retained the distal gains in addition to substantial improvements at the elbow and shoulder, resembling those of the unprimed group immediately after Wii-based Movement Therapy. It is possible that priming masked or delayed posttherapy improvements in proximal range of motion for the primed group. However, it is uncertain whether between-group differences in active range of motion are a direct consequence of priming or reflect the natural variability of the population with stroke and the inherent challenge of accurate joint goniometry after stroke.37 Assessments from week 28 indicate that bilateral priming may influence the retention of therapeutic effects as well as their magnitude. Monitoring during therapy and detailed histories at week 28 suggest that between-group differences at week 3 and week 28 were not due to disparities in patient compliance and real-world activity levels. The groups were well balanced for both adherence during therapy and for later continuation of self-directed therapy and/or return to real-world activities. The lack of any systematic differences between groups suggests that compliance, daily activity levels, and/or continuation of therapy activities were not confounding factors.

Methodological Considerations There is growing evidence to support the efficacy of both APBP and Wii-based Movement Therapy, although optimal therapy implementation is yet to be fully characterized for either. We saw no evidence of a correlation between the effect of priming and (1) patient age, (2) lesion location, or (3) time after stroke, suggesting that these parameters may have a limited influence on individual responsiveness to priming. In contrast, stratified FMA data suggest that baseline functional ability may influence priming efficacy, whereby patients with low motor function made the greatest gains (Figure 2). Significant spasticity at the wrists or digits was previously an exclusion criterion for APBP4,5 but not in the present study (n = 4). Bilateral priming was well tolerated by those with distal spasticity, although preliminary heat and passive stretching were applied before positioning in the priming device. Movement speed during priming was limited by spasticity, paresis, and bradykinesia in the present study, and this introduced considerable variability in the number of priming repetitions per session. It is not clear whether either movement speed or the number of repetitions is a critical factor for the efficacy of APBP. We saw no correlation between the number of priming repetitions and FMA improvements, suggesting that simply increasing the number of repetitions may not increase the net effect of priming. However, patients with the most priming repetitions had high motor function, and thus, their improvements may have been underestimated when using the FMA.36 Similarly, such patients may have less asymmetric inhibition to rebalance and hence less scope for priming-induced improvement. An unexpectedly high incidence of contraindications to transcranial magnetic stimulation (TMS) in our primed cohort (9/10) prevented neurophysiological investigations of priming-induced changes in cortical excitability and is a limitation of the present study. We can only hypothesize that similar cortical inhibitory changes to those previously reported4,5 were induced by bilateral priming in the present study, but how these interacted with underlying cortical changes induced by Wii-based Movement Therapy remains uncertain. We acknowledge that adopting a case-controlled design for the present study also has limitations. However, taking into account the sample size and inherent variability in the population with chronic stroke, this design circumvents the potential for significant differences between randomized patient groups at baseline, which may confound later comparisons.

Advantages of Bilateral Priming and Wii-Based Movement Therapy Both Wii-based Movement Therapy and APBP are inexpensive, portable, and suitable for home implementation,

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Shiner et al overcoming the rehabilitation limitations of geography,38 resources, and service availability.39,40 Growing evidence supports the benefits and suitability of Wii-based Movement Therapy for a diverse patient population, including those with little residual function after stroke who rarely receive conventional upper limb rehabilitation.27 The present study provides the first evidence that bilateral priming is also efficacious for patients with low or very low motor function after stroke. The active-passive design and inbuilt inertial advantage of APBP minimize fatigue to accommodate all patients after a stroke, including those with little or no voluntary movement of the more affected upper limb.4 Also, APBP is suitable for patients with contraindications to more conventional brain-priming strategies including those that use cortical stimulation.8,41-43 The high incidence of TMS contraindications encountered in the present study highlights the need for safe and effective priming alternatives. Rehabilitation strategies have diversified recently to include nontraditional methods of upper limb rehabilitation, such as bimanual upper limb training.44,45 While some studies suggest that bimanual therapies promote superior motor outcomes to unimanual interventions,46,47 the evidence is inconclusive,48 and the translation of bimanual therapy gains to everyday tasks is less successful than more conventional approaches.46,47 In the present study, we used Wiibased Movement Therapy as a unimanual therapeutic approach to reflect our primary focus on translating therapy gains to improved functional ability and quality of life. Bilateral priming was used as a rehabilitation adjuvant rather than a therapeutic intervention and as such is distinct from other bilateral or bimanual arm therapies. However, by combining a bilateral priming paradigm with a unilateral therapy, this protocol may confer some advantages of both bilateral and unilateral approaches to rehabilitation.45,49

Ancillary Benefits of Therapy Wii-based Movement Therapy benefits a broad spectrum of impairments after stroke, despite being specifically designed to target upper limb function.16,27,50 Balance and walking distance improved for both primed and unprimed patients after Wii-based Movement Therapy. The absence of a difference between groups for lower limb measures suggests that bilateral priming does not confer additional benefits for uninvolved limbs, nor does it impede generalized improvements promoted by subsequent therapy. Although the main objective of APBP is to facilitate use-dependent plasticity by rebalancing cortical inhibition, secondary therapeutic benefits for range of motion and muscle spasticity become evident. Patients with wrist spasticity (n = 4) liked the passive stretching received during priming movements. Although there were no significant changes in posttherapy spasticity assessed using the Tardieu Scale, it is possible that this assessment tool lacked the sensitivity to detect the

improvements in spasticity after APBP reported by patients. By encouraging an awareness of upper limb movement and coordinated controlled actions, bilateral priming also appeared to promote more purposeful and efficient movements bilaterally. In conclusion, this study provides preliminary evidence that a novel movement-based method of brain priming can enhance the efficacy of a novel upper limb rehabilitation protocol after stroke. Patients who received bilateral priming prior to Wii-based Movement Therapy had functional improvements assessed using the FMA that were approximately twice those of unprimed patients who received Wiibased Movement Therapy alone. This improvement was significantly better maintained at week 28, suggesting that APBP can enhance both the magnitude and retention of therapy-induced improvements after stroke. Declaration of Conflicting Interests The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Professor Byblow is a named inventor on a patent for a training device assigned to Uniservices Ltd. Ms Shiner and Dr McNulty declare no conflicts of interest.

Funding The author(s) received the following financial support for the research, authorship, and/or publication of this article: The authors gratefully acknowledge funding from the National Health and Medical Research Council of Australia and the New South Wales Office for Scientific and Medical Research of Australia.

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