- Email: [email protected]
Effects of Transcranial Direct Current Stimulation With Sensory Modulation on Stroke Motor Rehabilitation: A Randomized Controlled Trial
Accepted Manuscript Effects of Transcranial direct current stimulation with sensory modulation on stroke motor rehabilitation: A randomized controlled trial Chia-Lin Koh, PhD, Jau-Hong Lin, PhD, Jiann-Shing Jeng, MD, PhD, Sheau-Ling Huang, MS, Ching-Lin Hsieh, PhD PII:
S0003-9993(17)30420-3
DOI:
10.1016/j.apmr.2017.05.025
Reference:
YAPMR 56935
To appear in:
ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION
Received Date: 15 February 2017 Revised Date:
10 May 2017
Accepted Date: 25 May 2017
Please cite this article as: Koh C-L, Lin J-H, Jeng J-S, Huang S-L, Hsieh C-L, Effects of Transcranial direct current stimulation with sensory modulation on stroke motor rehabilitation: A randomized controlled trial, ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION (2017), doi: 10.1016/ j.apmr.2017.05.025. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Interventions for severe-moderate stroke
Effects of Transcranial direct current stimulation with sensory modulation on stroke motor rehabilitation: A randomized controlled trial
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Chia-Lin Koh, PhD;1 Jau-Hong Lin, PhD;2,3 Jiann-Shing Jeng, MD, PhD;4,5 Sheau-Ling Huang, MS;1,6* Ching-Lin Hsieh, PhD;1,6 1
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School of Occupational Therapy, College of Medicine, National Taiwan University, Taipei, Taiwan. 2 Department of Physical Therapy, College of Health Science, Kaohsiung Medical University, Kaohsiung, Taiwan 3 Department and Graduate Institute of Neurology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan 4 Department of Neurology, College of Medicine, National Taiwan University, Taipei, Taiwan. 5 Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan 6 Department of Physical Medicine and Rehabilitation, National Taiwan University Hospital, Taipei, Taiwan.
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The study was performed at the Department of Physical Medicine and Rehabilitation, National Taiwan University Hospital, Taipei, Taiwan.
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Sources of Funding: The study was supported by the Ministry of Science and Technology (NSC 101-2314-B-002-194-MY3), Taiwan Declaration of Conflicting Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01847157. Corresponding author: Sheau-Ling Huang, MS School of Occupational Therapy, College of Medicine, National Taiwan University Room 420, F4, No.17, Xuzhou Rd., Zhongzheng Dist., Taipei City 100, Taiwan TEL: +886 2 33668179 FAX: +886 2 23511331 Email: [email protected]
Interventions for severe-moderate stroke ACCEPTED MANUSCRIPT
Title
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Effects of Transcranial direct current stimulation with sensory modulation on
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stroke motor rehabilitation: A randomized controlled trial
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Abstract
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Objective: To test whether a multi-strategy intervention enhanced recovery
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immediately and longitudinally in patients with severe to moderate upper extremity
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(UE) paresis.
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Design: Double-blind randomized controlled trial with placebo control.
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Setting: An outpatient department of a local medical center.
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Participants: People (n = 25) with chronic stroke were randomly assigned to 2
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groups. Participants in the transcranial direct current stimulation with sensory
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modulation (tDCS-SM) and in the control group were 55.3±11.5 (n=14) and
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56.9±13.5 (n=11) years old, respectively.
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Interventions: 8-week intervention. The tDCS-SM group received bilateral tDCS,
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bilateral cutaneous anesthesia, and high repetitions of passive movements on the
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paretic hand. The control group received the same passive movements but with sham
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tDCS and sham anesthesia. During the experiment, all participants continued their
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regular rehabilitation.
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Main outcome measures: Voluntary UE movement, spasticity, UE function, and
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basic activities of daily living. Outcomes were assessed at baseline, at
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post-intervention, and at 3- and 6-month follow-ups.
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Results: No significant differences were found between groups. However, there was a
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Interventions for severe-moderate stroke ACCEPTED MANUSCRIPT trend that the voluntary UE movement improved more in the tDCS-SM group than in
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the control group, with a moderate immediate effect (partial η2, ηp2 = 0.14, p = 0.07)
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and moderate long-term effects (ηp2 =0.17, p = 0.05 and ηp2 = 0.12, p = 0.10).
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Compared with the control group, the tDCS-SM group had a trend of a small
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immediate effect (ηp2 = 0.02 – 0.04) on reducing spasticity but no long-term effect. A
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trend of small immediate and long-term effects in favor of tDCS-SM was found on
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UE function and daily function recovery (ηp2= 0.02 - 0.09).
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Conclusions: Accompanied with traditional rehabilitation, tDCS-SM had a
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non-significant trend of having immediate and longitudinal effects on voluntary UE
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movement recovery in patients with severe to moderate UE paresis after stroke, but its
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effects on spasticity reduction and functional recovery may be limited.
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(NCT01847157)
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Key words: Transcranial direct current stimulation; Anesthetics; Functional recovery;
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Stroke
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Abbreviations
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ARAT: Action Research Arm Test BI: Barthel Index FMA-UE: Fugl-Meyer Motor Assessment upper extremity subscale MAS: Modified Ashworth Scale
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NNT: number needed to treat tDCS-SM: transcranial direct current stimulation with sensory modulation UE: upper extremity
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Introduction
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About 60% of people with stroke suffer from severe to moderate motor impairments in an upper extremity (UE) in the chronic stage.1 The impaired voluntary
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UE movement often restricts an individual’s daily function and increases social
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burden.2 New effective interventions are needed to maximally facilitate motor
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recovery in patients with severe to moderate UE paresis after stroke.3
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Ward and Cohen4 suggested 5 possible strategies that may facilitate the recovery
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of a paretic hand:(1) reducing of somatosensory input from the intact hand to the brain;
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(2) increasing somatosensory input to the brain from the paretic hand; (3)
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anesthetizing the body part proximal to the paretic hand; (4) up-regulating activity of
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the affected motor cortex; and (5) down-regulating activity of the unaffected motor
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cortex. Positive effects were found in facilitating voluntary UE movement or UE
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function by one strategy intervention (mainly strategy 2, e.g., robotic training or
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mirror therapy where patients’ affected UE were passively moved) in patients with
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severe to moderate UE paresis.5, 6 Moreover, an intervention that combined cathodal
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transcranial direct current stimulation (strategy 5) with robot-assisted arm training
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(strategy 2) showed a small but significant effect on reducing UE spasticity in patients
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with severe to moderate UE paresis.7 Interventions combining multiple strategies may
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be more effective than a 1-strategy intervention for UE motor recovery after stroke.7-9
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Interventions for severe-moderate stroke ACCEPTED MANUSCRIPT However, no studies to date have examined the combined effect of the 5 strategies in
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patients with severe to moderate UE paresis. The immediate and long-term treatment
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effects of combining 5 strategies in patients with severe to moderate UE paresis were
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unknown.
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In this double-blind randomized control trial, we designed an intervention combining the aforementioned 5 strategies, named transcranial direct current
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stimulation with sensory modulation (tDCS-SM). We hypothesized that participants in
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the tDCS-SM group would show significant improvements on primary outcomes
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(voluntary UE movement and spasticity) and secondary outcomes (UE function and
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basic activities of daily living) when compared with a control group. The distal and
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proximal parts of the affected UE were treated as primary outcomes. The immediate
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and long-term effects of tDCS-SM were examined by comparison with a control
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group treated with strategy 2 (i.e., high repetitions of passive movements on the
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paretic hand with sham tDCS and sham anesthesia stimulation).
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Method
Participants characteristics This randomized controlled trial was conducted from January 2013 to June 2015 in a local medical center. People admitted to the rehabilitation department were 6
Interventions for severe-moderate stroke ACCEPTED MANUSCRIPT recruited if they met the following inclusion criteria: (1) severe to moderate UE
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hemiparesis (Fugl-Meyer Motor Assessment upper extremity subscale [FMA-UE]
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<50);10 (2) age of 20 to 80 years; (3) first-ever stroke between 6 months and 3 years
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before recruitment; (4) normal or slight impairment of sensory function (Fugl-Meyer
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sensory assessment, UE part >= 10; total score is 12) to avoid a confounding motor
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recovery effect; and (5) no more than moderate spasticity in the elbow flexor muscle
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(Modified Ashworth Scale [MAS] < 3).11 Participants were excluded from the study if
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they had the following conditions: (1) stroke lesions involving bilateral hemispheres;
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(2) contraindications to brain stimulation (such as metal implantations, seizures, or
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cardiac pacemakers);12 or (3) other neurological or orthopedic disorders that would
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influence the participants’ motor performance. This study was approved by the
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Research Ethics Committee Office of the local medical center and was registered with
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ClinicalTrials.gov (NCT01847157). Written informed consent was obtained from
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each participant after screening for eligibility.
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Procedure
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All eligible participants were randomly assigned to two groups using a
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computer-generated random number. The allocation of each participant was concealed
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in an envelope, which was given to the therapist who operated the tDCS machine. All
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participants were assessed by 2 independent therapists who were blinded to the 7
Interventions for severe-moderate stroke ACCEPTED MANUSCRIPT participants’ allocations, and the participants were unaware of their own allocations.
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Both assessors completed a 2-hour training course to become familiar with the
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standardized assessment procedures and scoring criteria. Each assessor practiced
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assessments on 10 patients with stroke and every assessment result was confirmed
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with an author who assessed the same patients independently. One hundred percent
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agreement was achieved before the assessors started formal evaluations. Outcome
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measures were assessed at baseline (within 3 days before intervention started),
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post-intervention (within 3 days after intervention finished), and at 3 and 6 months
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after intervention.
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Interventions
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All participants received their corresponding interventions in 30-minute sessions, 3 times a week, 1 day apart, for 8 weeks (a total of 24 sessions). All participants
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continued their regular rehabilitation programs in the medical center, including both
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occupational and physical therapy, and/or speech therapy when necessary.
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tDCS-SM group. The tDCS-SM consisted of 5 parts corresponding to Ward and
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Cohen’s 5 strategies4 simultaneously: bilateral tDCS stimulation (strategies 4 and 5),
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cutaneous anesthesia on both intact and affected hands (strategies 1 and 3), and
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passive repetitive wrist and finger movements (strategy 2) (Figure 1). The 5 parts
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were applied simultaneously. 8
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tDCS was applied for 30 minutes at an intensity of 1.5 mA using the Intelect® Mobile Combo (Chattanooga, USA) to provide constant current stimulation.13 Two 25
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cm2 electrodes with sponge surfaces were immersed in saline solution and then placed
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over the ipsilesional (anodal electrode) and the contralesional (cathodal electrode)
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primary motor cortex. The positions of the bilateral primary motor cortex were
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defined as C3/C4 according to the international 10-20 system of
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electroencephalograms.9 The protocol of tDCS we used followed common designs in
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previous studies and safety guidelines.13-15
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For cutaneous anesthesia, 15 g of anesthetic cream (Emla 5%, AstraZeneca) was applied to the ventral surface of the forearm of the unaffected side at a distance of
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1cm from the wrist, covering an area of 15 cm long x 5 cm wide.16 This anesthetic
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protocol has been found to improve motor performance in patients with stroke.16 In
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addition, 10 g of Emla 5% cream was applied to the ventral surface of the upper arm
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of the affected side at a distance of 1 cm from the elbow fossa, and over an area of 10
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cm long x 5 cm wide.
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Passive repetitive wrist and finger movements of the paretic hand were
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performed by a trained occupational therapist to maintain the consistency of the
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movements. All participants started with passive wrist extension/flexion first for 20
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minutes, followed by passive finger extension/flexion along with passive thumb 9
Interventions for severe-moderate stroke ACCEPTED MANUSCRIPT carpometacarpal joint abduction/adduction for 10 minutes. All movements were
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guided by a metronome set to a frequency of 1 Hz.17 Therefore, each participant
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would receive 1,200 repetitions of wrist extension/flexion movement and 600
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repetitions of finger extension/flexion movement. The high numbers of repetitions
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were recommended to optimize motor recovery.18
Control group. The equipment settings for the control intervention were exactly
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the same as those for the tDCS-SM group. Sham bilateral tDCS stimulation was
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provided by giving direct current for the first 30 seconds. This duration has been
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suggested to be effective in blinding participants to the intervention allocation without
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altering cortical excitability.9, 19 For the sham cutaneous anesthesia, a fragrance-free
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body cream similar in appearance to Emla cream was applied on the participants. The
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control group received the same passive repetitive wrist and finger movements as did
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the tDCS-SM group.
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Assessments
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Primary outcome. The FMA-UE is a 3-point standardized scale that measures
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voluntary UE movement (0-66).20 The shoulder, elbow, and forearm sections were
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calculated as proximal UE scores (0-36), and the wrist and finger sections, as distal
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UE scores (0-24). The MAS was used to evaluate spasticity in the elbow, wrist, and
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finger flexors of the affected upper limb, scoring on a 5-point scale (0 = no increase, 4 10
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= rigid).11 Both assessments have been found to have good reliability, validity, and
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responsiveness in patients with stroke.11, 21, 22
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Secondary outcome. The Action Research Arm Test (ARAT) was used to assess UE function (0-57).23 The Barthel Index (BI) assesses an individual's level of
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independence in basic activities of daily living (0-20).24 The ARAT and BI both have
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good reliability, validity, and responsiveness in patients with stroke.25-28
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Data analysis
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Sample size calculations were based on a previous study, which found that the change of FMA-UE after bilateral tDCS was 6.1 +/- 3.4 points.9 The change in the
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control group was 1.2 +/- 1.0 points. A minimum of n=8 per group was necessary to
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achieve a statistical power of at least 95% (2-tailed α= 0.05).
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Baseline characteristics were compared using Student t-tests for continuous variables and chi-squared tests for dichotomous variables. We performed
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intention-to-treat analysis, in which the baseline scores were used for dealing with
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missing data. Change scores were calculated between baseline and the 3 subsequent
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assessments (post-intervention, 3 and 6 months after intervention), respectively.
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Analysis of covariance (ANCOVA) was used to investigate the differences in change
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scores between the two groups, after baseline scores were adjusted. Because 4
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outcomes were investigated, we adjusted the alpha by dividing 0.05 by 4. Thus, the
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Interventions for severe-moderate stroke ACCEPTED MANUSCRIPT significance level was set at α = 0.013. A large effect was represented by a partial
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eta-square (ηp2) >= 0.26, a moderate effect by ηp2 >= 0.13, and a small effect by ηp2
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>= 0.02.29 To calculate the number needed to treat (NNT), a successful improvement
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was defined as having a change > 10% of the total score of the outcome measures.21
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Results
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Figure 2 shows the flow of participants’ enrollment in the study. A total of 618
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patients with stroke who were admitted to the rehabilitation ward were screened for
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eligibility. Of these, 572 (92%) were ineligible, with a majority having mild UE motor
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impairment (50%). The exclusions are listed in Figure 2. Twenty-five of the 46 (54%)
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eligible participants provided written informed consent and were randomly assigned
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into either the tDCS-SM group (n = 14) or the control group (n = 11). Details of the
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characteristics of the participants are shown in Table 1. No significant differences in
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the 2 groups were found in terms of age (p = 0.76), sex (p = 0.74), type of stroke (p =
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0.94), stroke chronicity (p = 0.49), or lesion side (p = 0.90). Only 1 participant in the
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control group dropped out before completing the intervention. A total of 5 (36%)
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participants in the tDCS-SM group and 1 (9%) participant in the control group
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dropped out during the follow-up period. A slight skin burn, a known side effect of
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tDCS,15 was noted in one person after a treatment session and the wound healed in a
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few days. No serious adverse effects were found.15 The baseline total FMA-UE score was significantly higher in the control group than in the tDCS-SM group (p = 0.04) (Table 2). We used ANCOVA to adjust for this
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baseline difference. For the other outcomes, no significant baseline differences were
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found between the two groups.
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Primary outcome: Motor control
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Fugl-Meyer Motor Assessment. Table 2 and Figure 3 show the intention-to-treat
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analysis results of the treatment effect of the tDCS-SM compared with the control
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group. The raw change score of the tDCS-SM group immediately after intervention
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was 5.8; that of the control group was 1.5. ANCOVA analysis after adjustment of the
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baseline scores revealed a non-significant trend of FMA-UE improvement in favor of
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tDCS-SM with a moderate effect size (ηp2 = 0.14, p = 0.07).The crude differences
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between the tDCS-SM group and the control group at 3 months and 6 months were
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5.2 and 3.8, respectively. The differences between groups were not statistically
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significant, but trends were found favoring the tDCS-SM with moderate effect sizes
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(ηp2 = 0.12 – 0.17, p = 0.05 - 0.10). The NNTs of tDCS-SM regarding FMA-UE at the
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3 assessment time points were 6, 31, and 5 (Table 3).
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Regarding FMA-UE proximal, a non-significant immediate effect was found for the tDCS-SM group with a small effect size compared with the control group (ηp2 = 13
Interventions for severe-moderate stroke ACCEPTED MANUSCRIPT 0.09, NNT = 3). The trend of treatment effect of tDCS-SM remained superior to the
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control at the 3- and 6-month follow-ups (ηp2 = 0.03 – 0.13) (NNT = 5 and 7,
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respectively). Regarding the treatment effect on distal UE, a non-significant
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immediate effect was found for the tDCS-SM group with a moderate effect size
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compared with the control group (ηp2 = 0.14) (NNT = 3). The trend of the treatment
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effect of tDCS-SM remained at the 3-month follow-up (ηp2 = 0.05; NNT = 22), but at
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the 6-month follow-up, the tDCS-SM group was no different from the control group
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(ηp2 = 0.01).
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Modified Ashworth Scale. No significant difference was found between groups in reducing UE spasticity immediately after the experiment or at follow-ups (p = 0.07 –
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0.84). Nonetheless, for the elbow flexors, a trend was found that the control group
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exhibited a small immediate treatment effect on reducing spasticity that was better
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than that of the tDCS-SM group (ηp2 = 0.02) (NNT = 31). No difference in treatment
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effect between the 2 groups was found at the 3-month follow-up (ηp2 < 0.01). A small
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between-group difference found at the 6-month follow-up (ηp2 = 0.04) resulted from
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an increase in elbow flexor spasticity (adjusted difference = 0.1) in the tDCS-SM
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group, while the control group maintained a reduction of spasticity.
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For the wrist and finger flexors, a trend was found that the tDCS-SM group had a small immediate effect that was better than that of the control group (ηp2 = 0.02 – 14
Interventions for severe-moderate stroke ACCEPTED MANUSCRIPT 0.04). The NNTs were 14 and 11. However, the spasticity of the wrist and finger
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flexors increased again in the tDCS-SM group at the 3- and 6-month follow-ups. The
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control group exhibited a trend of better long-term treatment effects on maintaining
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reduced wrist and finger spasticity (ηp2 = 0.03 – 0.14), except for finger spasticity at 6
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months follow-up (ηp2 < 0.01).
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Secondary outcome: UE and daily function
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Action Research Arm Test. A non-significant immediate effect on ARAT
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improvement was found for the tDCS-SM group with a small effect size compared
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with the control group (ηp2 = 0.02, p = 0.51). For the long-term treatment effect, a
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non-significant trend was found that the tDCS-SM group demonstrated a small
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treatment effect that was better than that of the control group (ηp2 = 0.04 and 0.09).
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The adjusted between-group differences were 4.5 and 1.4 in favor of the tDCS-SM
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group at the 3- and 6-month follow-up assessments.
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Barthel Index. The adjusted change scores of the BI were less than 1 point at all
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assessments in both groups. A non-significant immediate effect on BI improvement
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was found for the tDCS-SM group with a small effect size compared with the control
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group (ηp2 = 0.02, p = 0.53). The adjusted difference between the 2 groups was 0.3.
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No between-group difference was found at the 3-month follow-up (ηp2 = 0.01). At the
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6-month follow-up, a non-significant small treatment effect was found in favor of the 15
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control group (ηp2 = 0.09).
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Discussion
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We found a non-significant trend that, in patients with severe to moderate UE
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motor impairment after stroke, the improvement in voluntary UE movement was
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greater in the tDCS-SM intervention group than in the control intervention group.
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Moderate between-group effect sizes were found non-significantly for the immediate
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and 3-month follow-up treatment effects. The tDCS-SM group also exhibited a
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non-significant small effect at the 6-month follow-up than did the control group. The
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NNT of the immediate effect of the tDCS-SM was 6, indicating that about one in
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every 6 of the target patient group would benefit from the tDCS-SM as compared with
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the control group. Both bilateral tDCS and cutaneous anesthesia improved UE motor
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recovery in patients with stroke.8, 9, 16, 30 The effect of bilateral tDCS is due to motor
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cortical excitability modulation by changing neuron membrane potential,31 while that
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of cutaneous anesthesia may be due to the increase of short-interval intracortical
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inhibition in the contralateral motor cortex by blocking afferent input.32 Our results
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indicate that a combination of 5 strategies (the tDCS-SM group) may have a greater
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effect than a single strategy (the control group) on voluntary UE movement recovery
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in patients with severe to moderate UE paresis. The tDCS-SM has demonstrated its
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potential for improving UE motor recovery in patients with long-term severe to
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moderate UE paresis. Our results showed a non-significant trend that the tDCS-SM had small effects
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on reducing wrist and finger flexor spasticity as compared with the control
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intervention. These findings are consistent with those of a previous study.7 However,
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both wrist and finger flexor spasticity increased again at the follow-up assessments in
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the tDCS-SM group, but not in the control group. These results indicate that
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tDCS-SM may have immediate but not long-term effects on reducing hand spasticity.
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In addition, the majority of the NNTs for the tDCS-SM were larger than 10, indicating
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that the tDCS-SM may not be efficient for reducing spasticity in clinics. Because
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spasticity is a main cause of restriction of motor recovery, future studies on spasticity
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management are warranted.33
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tDCS-SM group is related to our method of intention-to-treat analysis. A total of 5
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participants (36%) were lost at the 6-month follow-up. Their MAS scores at follow-up
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were replaced by their own baseline scores, which were assumed to be the highest
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ones. Therefore, participants’ UE spasticity at follow-up may be overestimated.
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We found that tDCS-SM had a non-significant trend of larger effect on the distal than on the proximal part of the UE in both voluntary movement recovery and 17
Interventions for severe-moderate stroke ACCEPTED MANUSCRIPT spasticity reduction. This result corresponded to the design of the tDCS-SM: A large
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number of motor repetitions were given in the distal instead of the proximal part of
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the UE. Research has shown that neuronal plasticity is a use-dependent process34 that
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needs a high intensity of repetitions to consolidate synaptic connections.35 Our results
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demonstrated that high repetitions of movement (even in a passive manner) could
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enlarge the combined effects of tDCS and cutaneous anesthesia on motor recovery.
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Therefore, researchers and clinicians are advised to apply high repetitions of remedial
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or functional training along with tDCS and cutaneous anesthesia to maximize the
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training effect.
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On the functional outcomes (i.e., the ARAT and BI), a non-significant small between-group effect size was found in favor of the tDCS-SM group. However, the
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absolute score changes of both outcomes were less than 1 point in general, implying
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that real functional changes remained limited. The effect of tDCS-SM was not carried
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over to functional changes in patients with severe to moderate UE motor impairment.
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Although we designed our protocol based on previous studies, the protocol is not
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yet optimal for people with stroke. Further studies are needed to identify what
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combination of parameters of stimulation (e.g., stimulation intensity, session duration,
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interval between sessions) can maximize treatment effects on recovery in people with
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severe UE paresis. For example, a repetition of cathodal tDCS during the aftereffects 18
Interventions for severe-moderate stroke ACCEPTED MANUSCRIPT of a first stimulation session within 90 minutes has been shown to enhance
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tDCS-induced effects better than a daily interval in healthy adults.36 The sequence of
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intervention strategies might be another factor to consider. Applying tDCS before or
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after motor training has been found to induce opposite synaptic reactions.31 In
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addition, the characteristics (e.g., acute or subacute stage) of patients who may benefit
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most also require investigation. Our findings have opened up an opportunity to
321
increase motor recovery in people with severe UE paresis. Future works are warranted
322
to identify the best patient-matched treatment protocols to maximize patients'
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treatment outcomes.
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Three limitations may affect the interpretation of our findings. First, the individual effect of both tDCS and anesthesia in tDCS-SM is unknown because of the
326
lack of 2 control groups; i.e., real bilateral tDCS + sham anesthesia and sham bilateral
327
tDCS + real anesthesia along with passive movements. The treatment effect of
328
tDCS-SM could only be interpreted as a combined effect of all 5 strategies. Any
329
alternative combination needs further examination. Second, we excluded patients with
330
severe UE spasticity (MAS > 3) to avoid confounding the effect on voluntary
331
movement recovery. Whether tDCS-SM can remediate severe UE spasticity is worthy
332
of further investigation. Finally, all participants received similar amounts of
333
occupational and physical therapies 2 to 3 days per week in the same medical center,
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Interventions for severe-moderate stroke ACCEPTED MANUSCRIPT and we randomly assigned the participants. Nonetheless, the contents of these
335
therapies were not recorded or controlled. Thus, the effect of the participants’ regular
336
rehabilitation programs on our results is unknown. Future studies need to control the
337
potential effects of participants' regular treatment to confirm the treatment effects of
338
tDCS-SM.
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Conclusion
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Accompanied with traditional rehabilitation, tDCS-SM had a non-significant
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trend of having immediate and longitudinal effects on voluntary UE movement
343
recovery in patients with severe to moderate UE paresis after stroke. In terms of
344
spasticity control and functional changes, however, the tDCS-SM group was not
345
superior to the control group. We found that people with severe UE paresis still have
346
potential to recover. Future studies to optimize the treatment protocol are warranted.
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Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to the research,
authorship, and/or publication of this article.
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Interventions for severe-moderate stroke ACCEPTED MANUSCRIPT Fig 1. The transcranial direct current stimulation with sensory modulation intervention (tDCS-SM) for a right hemiplegic patient. tDCS-SM includes five
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strategies: (1) cutaneous anesthesia on the intact hand; (2) passive repetitive movements at the affected wrist and fingers; (3) cutaneous anesthesia on the affected
direct current stimulation.
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Fig 2. The patient enrollment flow diagram.
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proximal upper extremity; (4) anodal direct current stimulation; and (5) cathodal
Figure 3: Run charts of Fugl-Meyer Motor Assessment (FMA) scores at 4 assessment time points. Scores of total FMA upper extremity (UE) subscale (a), proximal UE (shoulder, elbow and forearm sections) (b), and distal UE (wrist and finger sections)
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(c) are shown. ηp2 = partial eta square. tDCS-SM = transcranial direct current
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stimulation with sensory modulation.
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ACCEPTED MANUSCRIPT Table 1. Characteristics of participants Patient
Age (year)
Sex
Type of stroke
Stroke chronicity (month)
Lesion side
tDCS-SM
t1
67.7
F
I
13.8
L
t2
48.1
F
I
15.8
R
t3
63.4
F
I
35.3
L
t4
58.7
F
H
10.8
L
t5
61.4
M
I
27.2
R
t6
46.7
F
I
7.7
R
t7
48.9
M
I
7.4
R
t8
44.6
M
H
14.4
L
t9
43.3
M
I
9.0
L
t10
71.8
M
I
17.4
L
t11
72.5
M
I
17.6
R
t12
63.1
F
I
23.8
L
t13
45.9
M
H
9.3
L
t14
38.6
M
H
11.6
R
I:H = 10:4
15.8 (8.1)
L:R = 8:6
I
8.1
L
I
10.1
L
I
7.7
R
Mean (SD) p-value
55.3 (11.4) F:M = 6:8
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40.1
F
64.4
M
61.1
M
c4 c5 c6 c7
72.2
F
H
14.0
R
44.4
M
H
12.1
L
68.8
M
I
38.4
L
46.4
M
I
6.7
L
c8 c9 c10 c11
44.4
M
H
8.7
L
41.4
F
I
10.5
R
69.1
F
I
22.6
R
73.5
M
I
8.0
R
I:H = 8:3
13.4 (9.4)
L:R = 6:5
0.942
0.494
0.897
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c1 c2 c3
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Control
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Mean (SD)
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56.9 (13.5) F:M = 4:7 0.756
0.742
F = female; H = hemorrhagic stroke; I = ischemic stroke; L = left; M = male; R = right; tDCS-SM = Transcranial direct
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Table 2. Intention-to-treat analysis of the treatment effect of tDCS-SM (n = 14) compared with control intervention (n = 11) ANCOVA
MAS Elbow flexor Wrist flexor Finger flexor ARAT BI
tDCS-SM Control tDCS-SM Control tDCS-SM Control
20.4 (6.2) 27.2 (9.4) 14.8 (5.3) 19.4 (6.6) 2.3 (2.2) 4.7 (5.5)
6.0 (1.5) 1.3 (1.8) 3.8 (0.9) 1.7 (1.0) 3.5 (0.7) 1.3 (0.8)
tDCS-SM
1.4 (0.7)
-0.1 (0.1)
Control tDCS-SM Control tDCS-SM
1.3 (0.3) 1.5 (0.6) 1.3 (0.6) 1.5 (1.0)
-0.2 (0.2) -0.3 (0.1) -0.1 (0.1) -0.4 (0.1)
Control tDCS-SM Control tDCS-SM
1.3 (0.9) 2.1 (2.1) 4.7 (9.1) 16.1 (4.1)
-0.2 (0.2) 0.5 (0.5) 0.0 (0.6) 0.3 (0.3)
Control
17.6 (2.2)
F
Partial Adjusted 2 η change (SE)
p
3.58 0.07
0.14
2.17 0.16
0.09
3.62 0.07
0.14
0.37 0.55
0.01
0.97 0.34
0.04
0.38 0.54
0.02
0.45 0.51
0.0 (0.3)
0.42 0.53
0.02 0.02
F
p
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Adjusted change (SE)
Post6m - Baseline Partial η2
Adjusted change (SE) 4.3 (1.5) 0.2 (1.7) 2.8 (1.0) 1.5 (1.1) 2.2 (0.8) 1.6 (0.9)
2.97 0.10
0.12
0.75 0.40
0.03
0.25 0.62
0.01
0.1 (0.1)
1.01 0.33
0.04
0.61 0.44
0.03
0.04 0.84
< 0.01
2.09 0.16
0.09
2.26 0.15
0.09
4.7 (1.7) -1.0 (2.0) 3.6 (1.1) 0.5 (1.2) 3.2 (0.8) 1.9 (0.9)
4.39 0.05
0.17
3.27 0.08
0.13
1.07 0.31
0.05
-0.1 (0.1)
0.11 0.74
< 0.01
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Mean (SD)
Post3m - Baseline
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Distal
Postimmediate - Baseline
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Proximal
Baseline
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FMA-UE Total*
Group
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Outcome
-0.1 (0.1) 0.1 (0.1) -0.1 (0.1) -0.2 (0.1) -0.5 (0.2) 5.0 (3.0) 0.5 (3.4) -0.3 (0.7) -0.7 (0.8)
3.66 0.07
0.14
2.06 0.17
0.09
0.96 0.34
0.04
0.13 0.72
0.01
-0.1 (0.2) 0.1 (0.1) -0.1 (0.1) -0.1 (0.2) -0.1 (0.2) 0.7 (0.6) -0.7 (0.7) 0.0 (0.3)
F
p
Partial η2
0.8 (0.4)
ARAT = Action research arm test; BI = Barthel index; FMA-UE = Fugl-Meyer Assessment, upper extremity subscale; MAS = modified Ashworth scale Main analyses use ANCOVA with baseline score as covariate. *Significant baseline differences between groups (p < 0.05)
ACCEPTED MANUSCRIPT Table 3. The number needed to treat of each primary outcome measure. Outcome
Improvements gained
Event rate
ARR (95%CI)
NNT (95% CI)
Control tDCS-SM (baseline n (baseline Control tDCS-SM = 11) n=14) FMA-UE Total
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Post-intervention 5
0.18
0.36
0.18 (-0.16, 0.51)
6 (1.9 - ∞)
Proximal Distal MAS Elbow flexor
2 1
8 8
0.18 0.09
0.57 0.57
0.39 (0.04, 0.73) 0.48 (0.17, 0.79)
3 (1.4, 22.5) 3 (1.3, 5.9)
9
11
0.82
0.79
0.03 (-0.28, 0.35)
31 (3.6 - ∞)
Wrist flexor Finger flexor
11 10
13 14
1.00 0.91
0.93 1.00
0.07 (-0.06, 0.21) 0.09 (-0.08, 0.26)
14 (15.8 - ∞) 11 (3.6 - ∞)
31 (3.6 - ∞) 5 (1.7 - ∞)
Distal MAS Elbow flexor Wrist flexor
5
7
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2
0.45
0.50
0.05 (-0.35, 0.44)
22 (2.3 - ∞)
10 10
10 13
0.91 0.91
0.71 0.93
0.19 (-0.10, 0.49) 0.02 (-0.20, 0.24)
6 (10.4 - ∞) 52 (4.2 - ∞)
Finger flexor
9
9
0.82
0.64
0.18 (-0.16, 0.51)
6 (6.1 - ∞)
3 months follow-up 9 2
11 6
0.82 0.18
0.79 0.43
0.03 (-0.28, 0.35) 0.25 (-0.10, 0.59)
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FMA-UE Total Proximal
FMA-UE Total
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6 months follow-up
0
3
0.00
0.21
0.21 (-0.07, 0.43)
5 (2.3 - ∞)
3 4
6 3
0.27 0.36
0.43 0.21
0.16 (-0.21, 0.53) 0.15 (-0.21, 0.51)
7 (1.9 - ∞) 7 (4.8 - ∞)
10 8
10 11
0.91 0.73
0.71 0.79
0.19 (-0.10, 0.49) 0.06 (-0.28, 0.40)
6 (10.4 - ∞) 18 (2.5 - ∞)
Finger flexor
8
14
0.73
1.00
0.27 (0.01, 0.54)
4 (1.9, 104.8)
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Proximal Distal MAS Elbow flexor Wrist flexor
ARR = Absolute Risk Reduction; FMA-UE = Fugl-Meyer Assessment, upper extremity subscale; MAS = modified Ashworth scale; NNT = Number Needed to Treat
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S0003-9993(17)30420-3
DOI:
10.1016/j.apmr.2017.05.025
Reference:
YAPMR 56935
To appear in:
ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION
Received Date: 15 February 2017 Revised Date:
10 May 2017
Accepted Date: 25 May 2017
Please cite this article as: Koh C-L, Lin J-H, Jeng J-S, Huang S-L, Hsieh C-L, Effects of Transcranial direct current stimulation with sensory modulation on stroke motor rehabilitation: A randomized controlled trial, ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION (2017), doi: 10.1016/ j.apmr.2017.05.025. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Interventions for severe-moderate stroke
Effects of Transcranial direct current stimulation with sensory modulation on stroke motor rehabilitation: A randomized controlled trial
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Chia-Lin Koh, PhD;1 Jau-Hong Lin, PhD;2,3 Jiann-Shing Jeng, MD, PhD;4,5 Sheau-Ling Huang, MS;1,6* Ching-Lin Hsieh, PhD;1,6 1
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School of Occupational Therapy, College of Medicine, National Taiwan University, Taipei, Taiwan. 2 Department of Physical Therapy, College of Health Science, Kaohsiung Medical University, Kaohsiung, Taiwan 3 Department and Graduate Institute of Neurology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan 4 Department of Neurology, College of Medicine, National Taiwan University, Taipei, Taiwan. 5 Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan 6 Department of Physical Medicine and Rehabilitation, National Taiwan University Hospital, Taipei, Taiwan.
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The study was performed at the Department of Physical Medicine and Rehabilitation, National Taiwan University Hospital, Taipei, Taiwan.
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Sources of Funding: The study was supported by the Ministry of Science and Technology (NSC 101-2314-B-002-194-MY3), Taiwan Declaration of Conflicting Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01847157. Corresponding author: Sheau-Ling Huang, MS School of Occupational Therapy, College of Medicine, National Taiwan University Room 420, F4, No.17, Xuzhou Rd., Zhongzheng Dist., Taipei City 100, Taiwan TEL: +886 2 33668179 FAX: +886 2 23511331 Email: [email protected]
Interventions for severe-moderate stroke ACCEPTED MANUSCRIPT
Title
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Effects of Transcranial direct current stimulation with sensory modulation on
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stroke motor rehabilitation: A randomized controlled trial
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Abstract
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Objective: To test whether a multi-strategy intervention enhanced recovery
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immediately and longitudinally in patients with severe to moderate upper extremity
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(UE) paresis.
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Design: Double-blind randomized controlled trial with placebo control.
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Setting: An outpatient department of a local medical center.
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Participants: People (n = 25) with chronic stroke were randomly assigned to 2
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groups. Participants in the transcranial direct current stimulation with sensory
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modulation (tDCS-SM) and in the control group were 55.3±11.5 (n=14) and
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56.9±13.5 (n=11) years old, respectively.
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Interventions: 8-week intervention. The tDCS-SM group received bilateral tDCS,
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bilateral cutaneous anesthesia, and high repetitions of passive movements on the
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paretic hand. The control group received the same passive movements but with sham
17
tDCS and sham anesthesia. During the experiment, all participants continued their
18
regular rehabilitation.
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Main outcome measures: Voluntary UE movement, spasticity, UE function, and
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basic activities of daily living. Outcomes were assessed at baseline, at
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post-intervention, and at 3- and 6-month follow-ups.
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Results: No significant differences were found between groups. However, there was a
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Interventions for severe-moderate stroke ACCEPTED MANUSCRIPT trend that the voluntary UE movement improved more in the tDCS-SM group than in
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the control group, with a moderate immediate effect (partial η2, ηp2 = 0.14, p = 0.07)
25
and moderate long-term effects (ηp2 =0.17, p = 0.05 and ηp2 = 0.12, p = 0.10).
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Compared with the control group, the tDCS-SM group had a trend of a small
27
immediate effect (ηp2 = 0.02 – 0.04) on reducing spasticity but no long-term effect. A
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trend of small immediate and long-term effects in favor of tDCS-SM was found on
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UE function and daily function recovery (ηp2= 0.02 - 0.09).
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Conclusions: Accompanied with traditional rehabilitation, tDCS-SM had a
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non-significant trend of having immediate and longitudinal effects on voluntary UE
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movement recovery in patients with severe to moderate UE paresis after stroke, but its
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effects on spasticity reduction and functional recovery may be limited.
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(NCT01847157)
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Key words: Transcranial direct current stimulation; Anesthetics; Functional recovery;
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Stroke
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Interventions for severe-moderate stroke ACCEPTED MANUSCRIPT
Abbreviations
39 ANCOVA: Analysis of covariance
41 42 43 44
ARAT: Action Research Arm Test BI: Barthel Index FMA-UE: Fugl-Meyer Motor Assessment upper extremity subscale MAS: Modified Ashworth Scale
45 46 47 48
NNT: number needed to treat tDCS-SM: transcranial direct current stimulation with sensory modulation UE: upper extremity
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Introduction
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About 60% of people with stroke suffer from severe to moderate motor impairments in an upper extremity (UE) in the chronic stage.1 The impaired voluntary
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UE movement often restricts an individual’s daily function and increases social
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burden.2 New effective interventions are needed to maximally facilitate motor
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recovery in patients with severe to moderate UE paresis after stroke.3
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Ward and Cohen4 suggested 5 possible strategies that may facilitate the recovery
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of a paretic hand:(1) reducing of somatosensory input from the intact hand to the brain;
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(2) increasing somatosensory input to the brain from the paretic hand; (3)
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anesthetizing the body part proximal to the paretic hand; (4) up-regulating activity of
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the affected motor cortex; and (5) down-regulating activity of the unaffected motor
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cortex. Positive effects were found in facilitating voluntary UE movement or UE
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function by one strategy intervention (mainly strategy 2, e.g., robotic training or
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mirror therapy where patients’ affected UE were passively moved) in patients with
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severe to moderate UE paresis.5, 6 Moreover, an intervention that combined cathodal
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transcranial direct current stimulation (strategy 5) with robot-assisted arm training
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(strategy 2) showed a small but significant effect on reducing UE spasticity in patients
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with severe to moderate UE paresis.7 Interventions combining multiple strategies may
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be more effective than a 1-strategy intervention for UE motor recovery after stroke.7-9
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Interventions for severe-moderate stroke ACCEPTED MANUSCRIPT However, no studies to date have examined the combined effect of the 5 strategies in
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patients with severe to moderate UE paresis. The immediate and long-term treatment
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effects of combining 5 strategies in patients with severe to moderate UE paresis were
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unknown.
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In this double-blind randomized control trial, we designed an intervention combining the aforementioned 5 strategies, named transcranial direct current
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stimulation with sensory modulation (tDCS-SM). We hypothesized that participants in
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the tDCS-SM group would show significant improvements on primary outcomes
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(voluntary UE movement and spasticity) and secondary outcomes (UE function and
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basic activities of daily living) when compared with a control group. The distal and
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proximal parts of the affected UE were treated as primary outcomes. The immediate
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and long-term effects of tDCS-SM were examined by comparison with a control
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group treated with strategy 2 (i.e., high repetitions of passive movements on the
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paretic hand with sham tDCS and sham anesthesia stimulation).
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Method
Participants characteristics This randomized controlled trial was conducted from January 2013 to June 2015 in a local medical center. People admitted to the rehabilitation department were 6
Interventions for severe-moderate stroke ACCEPTED MANUSCRIPT recruited if they met the following inclusion criteria: (1) severe to moderate UE
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hemiparesis (Fugl-Meyer Motor Assessment upper extremity subscale [FMA-UE]
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<50);10 (2) age of 20 to 80 years; (3) first-ever stroke between 6 months and 3 years
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before recruitment; (4) normal or slight impairment of sensory function (Fugl-Meyer
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sensory assessment, UE part >= 10; total score is 12) to avoid a confounding motor
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recovery effect; and (5) no more than moderate spasticity in the elbow flexor muscle
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(Modified Ashworth Scale [MAS] < 3).11 Participants were excluded from the study if
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they had the following conditions: (1) stroke lesions involving bilateral hemispheres;
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(2) contraindications to brain stimulation (such as metal implantations, seizures, or
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cardiac pacemakers);12 or (3) other neurological or orthopedic disorders that would
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influence the participants’ motor performance. This study was approved by the
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Research Ethics Committee Office of the local medical center and was registered with
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ClinicalTrials.gov (NCT01847157). Written informed consent was obtained from
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each participant after screening for eligibility.
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Procedure
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All eligible participants were randomly assigned to two groups using a
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computer-generated random number. The allocation of each participant was concealed
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in an envelope, which was given to the therapist who operated the tDCS machine. All
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participants were assessed by 2 independent therapists who were blinded to the 7
Interventions for severe-moderate stroke ACCEPTED MANUSCRIPT participants’ allocations, and the participants were unaware of their own allocations.
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Both assessors completed a 2-hour training course to become familiar with the
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standardized assessment procedures and scoring criteria. Each assessor practiced
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assessments on 10 patients with stroke and every assessment result was confirmed
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with an author who assessed the same patients independently. One hundred percent
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agreement was achieved before the assessors started formal evaluations. Outcome
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measures were assessed at baseline (within 3 days before intervention started),
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post-intervention (within 3 days after intervention finished), and at 3 and 6 months
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after intervention.
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Interventions
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All participants received their corresponding interventions in 30-minute sessions, 3 times a week, 1 day apart, for 8 weeks (a total of 24 sessions). All participants
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continued their regular rehabilitation programs in the medical center, including both
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occupational and physical therapy, and/or speech therapy when necessary.
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tDCS-SM group. The tDCS-SM consisted of 5 parts corresponding to Ward and
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Cohen’s 5 strategies4 simultaneously: bilateral tDCS stimulation (strategies 4 and 5),
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cutaneous anesthesia on both intact and affected hands (strategies 1 and 3), and
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passive repetitive wrist and finger movements (strategy 2) (Figure 1). The 5 parts
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were applied simultaneously. 8
Interventions for severe-moderate stroke ACCEPTED MANUSCRIPT 125
tDCS was applied for 30 minutes at an intensity of 1.5 mA using the Intelect® Mobile Combo (Chattanooga, USA) to provide constant current stimulation.13 Two 25
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cm2 electrodes with sponge surfaces were immersed in saline solution and then placed
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over the ipsilesional (anodal electrode) and the contralesional (cathodal electrode)
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primary motor cortex. The positions of the bilateral primary motor cortex were
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defined as C3/C4 according to the international 10-20 system of
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electroencephalograms.9 The protocol of tDCS we used followed common designs in
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previous studies and safety guidelines.13-15
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For cutaneous anesthesia, 15 g of anesthetic cream (Emla 5%, AstraZeneca) was applied to the ventral surface of the forearm of the unaffected side at a distance of
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1cm from the wrist, covering an area of 15 cm long x 5 cm wide.16 This anesthetic
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protocol has been found to improve motor performance in patients with stroke.16 In
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addition, 10 g of Emla 5% cream was applied to the ventral surface of the upper arm
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of the affected side at a distance of 1 cm from the elbow fossa, and over an area of 10
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cm long x 5 cm wide.
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Passive repetitive wrist and finger movements of the paretic hand were
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performed by a trained occupational therapist to maintain the consistency of the
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movements. All participants started with passive wrist extension/flexion first for 20
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minutes, followed by passive finger extension/flexion along with passive thumb 9
Interventions for severe-moderate stroke ACCEPTED MANUSCRIPT carpometacarpal joint abduction/adduction for 10 minutes. All movements were
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guided by a metronome set to a frequency of 1 Hz.17 Therefore, each participant
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would receive 1,200 repetitions of wrist extension/flexion movement and 600
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repetitions of finger extension/flexion movement. The high numbers of repetitions
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were recommended to optimize motor recovery.18
Control group. The equipment settings for the control intervention were exactly
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the same as those for the tDCS-SM group. Sham bilateral tDCS stimulation was
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provided by giving direct current for the first 30 seconds. This duration has been
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suggested to be effective in blinding participants to the intervention allocation without
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altering cortical excitability.9, 19 For the sham cutaneous anesthesia, a fragrance-free
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body cream similar in appearance to Emla cream was applied on the participants. The
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control group received the same passive repetitive wrist and finger movements as did
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the tDCS-SM group.
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Assessments
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Primary outcome. The FMA-UE is a 3-point standardized scale that measures
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voluntary UE movement (0-66).20 The shoulder, elbow, and forearm sections were
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calculated as proximal UE scores (0-36), and the wrist and finger sections, as distal
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UE scores (0-24). The MAS was used to evaluate spasticity in the elbow, wrist, and
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finger flexors of the affected upper limb, scoring on a 5-point scale (0 = no increase, 4 10
Interventions for severe-moderate stroke ACCEPTED MANUSCRIPT 163
= rigid).11 Both assessments have been found to have good reliability, validity, and
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responsiveness in patients with stroke.11, 21, 22
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Secondary outcome. The Action Research Arm Test (ARAT) was used to assess UE function (0-57).23 The Barthel Index (BI) assesses an individual's level of
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independence in basic activities of daily living (0-20).24 The ARAT and BI both have
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good reliability, validity, and responsiveness in patients with stroke.25-28
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Data analysis
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Sample size calculations were based on a previous study, which found that the change of FMA-UE after bilateral tDCS was 6.1 +/- 3.4 points.9 The change in the
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control group was 1.2 +/- 1.0 points. A minimum of n=8 per group was necessary to
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achieve a statistical power of at least 95% (2-tailed α= 0.05).
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Baseline characteristics were compared using Student t-tests for continuous variables and chi-squared tests for dichotomous variables. We performed
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intention-to-treat analysis, in which the baseline scores were used for dealing with
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missing data. Change scores were calculated between baseline and the 3 subsequent
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assessments (post-intervention, 3 and 6 months after intervention), respectively.
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Analysis of covariance (ANCOVA) was used to investigate the differences in change
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scores between the two groups, after baseline scores were adjusted. Because 4
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outcomes were investigated, we adjusted the alpha by dividing 0.05 by 4. Thus, the
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11
Interventions for severe-moderate stroke ACCEPTED MANUSCRIPT significance level was set at α = 0.013. A large effect was represented by a partial
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eta-square (ηp2) >= 0.26, a moderate effect by ηp2 >= 0.13, and a small effect by ηp2
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>= 0.02.29 To calculate the number needed to treat (NNT), a successful improvement
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was defined as having a change > 10% of the total score of the outcome measures.21
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Results
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Figure 2 shows the flow of participants’ enrollment in the study. A total of 618
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patients with stroke who were admitted to the rehabilitation ward were screened for
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eligibility. Of these, 572 (92%) were ineligible, with a majority having mild UE motor
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impairment (50%). The exclusions are listed in Figure 2. Twenty-five of the 46 (54%)
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eligible participants provided written informed consent and were randomly assigned
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into either the tDCS-SM group (n = 14) or the control group (n = 11). Details of the
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characteristics of the participants are shown in Table 1. No significant differences in
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the 2 groups were found in terms of age (p = 0.76), sex (p = 0.74), type of stroke (p =
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0.94), stroke chronicity (p = 0.49), or lesion side (p = 0.90). Only 1 participant in the
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control group dropped out before completing the intervention. A total of 5 (36%)
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participants in the tDCS-SM group and 1 (9%) participant in the control group
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dropped out during the follow-up period. A slight skin burn, a known side effect of
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tDCS,15 was noted in one person after a treatment session and the wound healed in a
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Interventions for severe-moderate stroke ACCEPTED MANUSCRIPT 201 202
few days. No serious adverse effects were found.15 The baseline total FMA-UE score was significantly higher in the control group than in the tDCS-SM group (p = 0.04) (Table 2). We used ANCOVA to adjust for this
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baseline difference. For the other outcomes, no significant baseline differences were
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found between the two groups.
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Primary outcome: Motor control
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Fugl-Meyer Motor Assessment. Table 2 and Figure 3 show the intention-to-treat
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analysis results of the treatment effect of the tDCS-SM compared with the control
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group. The raw change score of the tDCS-SM group immediately after intervention
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was 5.8; that of the control group was 1.5. ANCOVA analysis after adjustment of the
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baseline scores revealed a non-significant trend of FMA-UE improvement in favor of
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tDCS-SM with a moderate effect size (ηp2 = 0.14, p = 0.07).The crude differences
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between the tDCS-SM group and the control group at 3 months and 6 months were
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5.2 and 3.8, respectively. The differences between groups were not statistically
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significant, but trends were found favoring the tDCS-SM with moderate effect sizes
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(ηp2 = 0.12 – 0.17, p = 0.05 - 0.10). The NNTs of tDCS-SM regarding FMA-UE at the
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3 assessment time points were 6, 31, and 5 (Table 3).
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Regarding FMA-UE proximal, a non-significant immediate effect was found for the tDCS-SM group with a small effect size compared with the control group (ηp2 = 13
Interventions for severe-moderate stroke ACCEPTED MANUSCRIPT 0.09, NNT = 3). The trend of treatment effect of tDCS-SM remained superior to the
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control at the 3- and 6-month follow-ups (ηp2 = 0.03 – 0.13) (NNT = 5 and 7,
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respectively). Regarding the treatment effect on distal UE, a non-significant
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immediate effect was found for the tDCS-SM group with a moderate effect size
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compared with the control group (ηp2 = 0.14) (NNT = 3). The trend of the treatment
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effect of tDCS-SM remained at the 3-month follow-up (ηp2 = 0.05; NNT = 22), but at
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the 6-month follow-up, the tDCS-SM group was no different from the control group
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(ηp2 = 0.01).
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Modified Ashworth Scale. No significant difference was found between groups in reducing UE spasticity immediately after the experiment or at follow-ups (p = 0.07 –
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0.84). Nonetheless, for the elbow flexors, a trend was found that the control group
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exhibited a small immediate treatment effect on reducing spasticity that was better
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than that of the tDCS-SM group (ηp2 = 0.02) (NNT = 31). No difference in treatment
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effect between the 2 groups was found at the 3-month follow-up (ηp2 < 0.01). A small
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between-group difference found at the 6-month follow-up (ηp2 = 0.04) resulted from
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an increase in elbow flexor spasticity (adjusted difference = 0.1) in the tDCS-SM
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group, while the control group maintained a reduction of spasticity.
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For the wrist and finger flexors, a trend was found that the tDCS-SM group had a small immediate effect that was better than that of the control group (ηp2 = 0.02 – 14
Interventions for severe-moderate stroke ACCEPTED MANUSCRIPT 0.04). The NNTs were 14 and 11. However, the spasticity of the wrist and finger
240
flexors increased again in the tDCS-SM group at the 3- and 6-month follow-ups. The
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control group exhibited a trend of better long-term treatment effects on maintaining
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reduced wrist and finger spasticity (ηp2 = 0.03 – 0.14), except for finger spasticity at 6
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months follow-up (ηp2 < 0.01).
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Secondary outcome: UE and daily function
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Action Research Arm Test. A non-significant immediate effect on ARAT
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improvement was found for the tDCS-SM group with a small effect size compared
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with the control group (ηp2 = 0.02, p = 0.51). For the long-term treatment effect, a
248
non-significant trend was found that the tDCS-SM group demonstrated a small
249
treatment effect that was better than that of the control group (ηp2 = 0.04 and 0.09).
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The adjusted between-group differences were 4.5 and 1.4 in favor of the tDCS-SM
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group at the 3- and 6-month follow-up assessments.
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Barthel Index. The adjusted change scores of the BI were less than 1 point at all
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assessments in both groups. A non-significant immediate effect on BI improvement
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was found for the tDCS-SM group with a small effect size compared with the control
255
group (ηp2 = 0.02, p = 0.53). The adjusted difference between the 2 groups was 0.3.
256
No between-group difference was found at the 3-month follow-up (ηp2 = 0.01). At the
257
6-month follow-up, a non-significant small treatment effect was found in favor of the 15
Interventions for severe-moderate stroke ACCEPTED MANUSCRIPT 258
control group (ηp2 = 0.09).
259
Discussion
261
We found a non-significant trend that, in patients with severe to moderate UE
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motor impairment after stroke, the improvement in voluntary UE movement was
263
greater in the tDCS-SM intervention group than in the control intervention group.
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Moderate between-group effect sizes were found non-significantly for the immediate
265
and 3-month follow-up treatment effects. The tDCS-SM group also exhibited a
266
non-significant small effect at the 6-month follow-up than did the control group. The
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NNT of the immediate effect of the tDCS-SM was 6, indicating that about one in
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every 6 of the target patient group would benefit from the tDCS-SM as compared with
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the control group. Both bilateral tDCS and cutaneous anesthesia improved UE motor
270
recovery in patients with stroke.8, 9, 16, 30 The effect of bilateral tDCS is due to motor
271
cortical excitability modulation by changing neuron membrane potential,31 while that
272
of cutaneous anesthesia may be due to the increase of short-interval intracortical
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inhibition in the contralateral motor cortex by blocking afferent input.32 Our results
274
indicate that a combination of 5 strategies (the tDCS-SM group) may have a greater
275
effect than a single strategy (the control group) on voluntary UE movement recovery
276
in patients with severe to moderate UE paresis. The tDCS-SM has demonstrated its
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Interventions for severe-moderate stroke ACCEPTED MANUSCRIPT 277
potential for improving UE motor recovery in patients with long-term severe to
278
moderate UE paresis. Our results showed a non-significant trend that the tDCS-SM had small effects
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on reducing wrist and finger flexor spasticity as compared with the control
281
intervention. These findings are consistent with those of a previous study.7 However,
282
both wrist and finger flexor spasticity increased again at the follow-up assessments in
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the tDCS-SM group, but not in the control group. These results indicate that
284
tDCS-SM may have immediate but not long-term effects on reducing hand spasticity.
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In addition, the majority of the NNTs for the tDCS-SM were larger than 10, indicating
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that the tDCS-SM may not be efficient for reducing spasticity in clinics. Because
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spasticity is a main cause of restriction of motor recovery, future studies on spasticity
288
management are warranted.33
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tDCS-SM group is related to our method of intention-to-treat analysis. A total of 5
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participants (36%) were lost at the 6-month follow-up. Their MAS scores at follow-up
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were replaced by their own baseline scores, which were assumed to be the highest
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ones. Therefore, participants’ UE spasticity at follow-up may be overestimated.
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We found that tDCS-SM had a non-significant trend of larger effect on the distal than on the proximal part of the UE in both voluntary movement recovery and 17
Interventions for severe-moderate stroke ACCEPTED MANUSCRIPT spasticity reduction. This result corresponded to the design of the tDCS-SM: A large
297
number of motor repetitions were given in the distal instead of the proximal part of
298
the UE. Research has shown that neuronal plasticity is a use-dependent process34 that
299
needs a high intensity of repetitions to consolidate synaptic connections.35 Our results
300
demonstrated that high repetitions of movement (even in a passive manner) could
301
enlarge the combined effects of tDCS and cutaneous anesthesia on motor recovery.
302
Therefore, researchers and clinicians are advised to apply high repetitions of remedial
303
or functional training along with tDCS and cutaneous anesthesia to maximize the
304
training effect.
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On the functional outcomes (i.e., the ARAT and BI), a non-significant small between-group effect size was found in favor of the tDCS-SM group. However, the
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absolute score changes of both outcomes were less than 1 point in general, implying
308
that real functional changes remained limited. The effect of tDCS-SM was not carried
309
over to functional changes in patients with severe to moderate UE motor impairment.
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Although we designed our protocol based on previous studies, the protocol is not
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yet optimal for people with stroke. Further studies are needed to identify what
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combination of parameters of stimulation (e.g., stimulation intensity, session duration,
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interval between sessions) can maximize treatment effects on recovery in people with
314
severe UE paresis. For example, a repetition of cathodal tDCS during the aftereffects 18
Interventions for severe-moderate stroke ACCEPTED MANUSCRIPT of a first stimulation session within 90 minutes has been shown to enhance
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tDCS-induced effects better than a daily interval in healthy adults.36 The sequence of
317
intervention strategies might be another factor to consider. Applying tDCS before or
318
after motor training has been found to induce opposite synaptic reactions.31 In
319
addition, the characteristics (e.g., acute or subacute stage) of patients who may benefit
320
most also require investigation. Our findings have opened up an opportunity to
321
increase motor recovery in people with severe UE paresis. Future works are warranted
322
to identify the best patient-matched treatment protocols to maximize patients'
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treatment outcomes.
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Three limitations may affect the interpretation of our findings. First, the individual effect of both tDCS and anesthesia in tDCS-SM is unknown because of the
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lack of 2 control groups; i.e., real bilateral tDCS + sham anesthesia and sham bilateral
327
tDCS + real anesthesia along with passive movements. The treatment effect of
328
tDCS-SM could only be interpreted as a combined effect of all 5 strategies. Any
329
alternative combination needs further examination. Second, we excluded patients with
330
severe UE spasticity (MAS > 3) to avoid confounding the effect on voluntary
331
movement recovery. Whether tDCS-SM can remediate severe UE spasticity is worthy
332
of further investigation. Finally, all participants received similar amounts of
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occupational and physical therapies 2 to 3 days per week in the same medical center,
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therapies were not recorded or controlled. Thus, the effect of the participants’ regular
336
rehabilitation programs on our results is unknown. Future studies need to control the
337
potential effects of participants' regular treatment to confirm the treatment effects of
338
tDCS-SM.
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Conclusion
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Accompanied with traditional rehabilitation, tDCS-SM had a non-significant
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trend of having immediate and longitudinal effects on voluntary UE movement
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recovery in patients with severe to moderate UE paresis after stroke. In terms of
344
spasticity control and functional changes, however, the tDCS-SM group was not
345
superior to the control group. We found that people with severe UE paresis still have
346
potential to recover. Future studies to optimize the treatment protocol are warranted.
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Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to the research,
authorship, and/or publication of this article.
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Interventions for severe-moderate stroke ACCEPTED MANUSCRIPT Fig 1. The transcranial direct current stimulation with sensory modulation intervention (tDCS-SM) for a right hemiplegic patient. tDCS-SM includes five
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strategies: (1) cutaneous anesthesia on the intact hand; (2) passive repetitive movements at the affected wrist and fingers; (3) cutaneous anesthesia on the affected
direct current stimulation.
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Fig 2. The patient enrollment flow diagram.
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proximal upper extremity; (4) anodal direct current stimulation; and (5) cathodal
Figure 3: Run charts of Fugl-Meyer Motor Assessment (FMA) scores at 4 assessment time points. Scores of total FMA upper extremity (UE) subscale (a), proximal UE (shoulder, elbow and forearm sections) (b), and distal UE (wrist and finger sections)
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(c) are shown. ηp2 = partial eta square. tDCS-SM = transcranial direct current
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stimulation with sensory modulation.
27
ACCEPTED MANUSCRIPT Table 1. Characteristics of participants Patient
Age (year)
Sex
Type of stroke
Stroke chronicity (month)
Lesion side
tDCS-SM
t1
67.7
F
I
13.8
L
t2
48.1
F
I
15.8
R
t3
63.4
F
I
35.3
L
t4
58.7
F
H
10.8
L
t5
61.4
M
I
27.2
R
t6
46.7
F
I
7.7
R
t7
48.9
M
I
7.4
R
t8
44.6
M
H
14.4
L
t9
43.3
M
I
9.0
L
t10
71.8
M
I
17.4
L
t11
72.5
M
I
17.6
R
t12
63.1
F
I
23.8
L
t13
45.9
M
H
9.3
L
t14
38.6
M
H
11.6
R
I:H = 10:4
15.8 (8.1)
L:R = 8:6
I
8.1
L
I
10.1
L
I
7.7
R
Mean (SD) p-value
55.3 (11.4) F:M = 6:8
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40.1
F
64.4
M
61.1
M
c4 c5 c6 c7
72.2
F
H
14.0
R
44.4
M
H
12.1
L
68.8
M
I
38.4
L
46.4
M
I
6.7
L
c8 c9 c10 c11
44.4
M
H
8.7
L
41.4
F
I
10.5
R
69.1
F
I
22.6
R
73.5
M
I
8.0
R
I:H = 8:3
13.4 (9.4)
L:R = 6:5
0.942
0.494
0.897
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c1 c2 c3
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Control
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Mean (SD)
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Group
56.9 (13.5) F:M = 4:7 0.756
0.742
F = female; H = hemorrhagic stroke; I = ischemic stroke; L = left; M = male; R = right; tDCS-SM = Transcranial direct
current stimulation with sensory modulation intervention
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Table 2. Intention-to-treat analysis of the treatment effect of tDCS-SM (n = 14) compared with control intervention (n = 11) ANCOVA
MAS Elbow flexor Wrist flexor Finger flexor ARAT BI
tDCS-SM Control tDCS-SM Control tDCS-SM Control
20.4 (6.2) 27.2 (9.4) 14.8 (5.3) 19.4 (6.6) 2.3 (2.2) 4.7 (5.5)
6.0 (1.5) 1.3 (1.8) 3.8 (0.9) 1.7 (1.0) 3.5 (0.7) 1.3 (0.8)
tDCS-SM
1.4 (0.7)
-0.1 (0.1)
Control tDCS-SM Control tDCS-SM
1.3 (0.3) 1.5 (0.6) 1.3 (0.6) 1.5 (1.0)
-0.2 (0.2) -0.3 (0.1) -0.1 (0.1) -0.4 (0.1)
Control tDCS-SM Control tDCS-SM
1.3 (0.9) 2.1 (2.1) 4.7 (9.1) 16.1 (4.1)
-0.2 (0.2) 0.5 (0.5) 0.0 (0.6) 0.3 (0.3)
Control
17.6 (2.2)
F
Partial Adjusted 2 η change (SE)
p
3.58 0.07
0.14
2.17 0.16
0.09
3.62 0.07
0.14
0.37 0.55
0.01
0.97 0.34
0.04
0.38 0.54
0.02
0.45 0.51
0.0 (0.3)
0.42 0.53
0.02 0.02
F
p
RI PT
Adjusted change (SE)
Post6m - Baseline Partial η2
Adjusted change (SE) 4.3 (1.5) 0.2 (1.7) 2.8 (1.0) 1.5 (1.1) 2.2 (0.8) 1.6 (0.9)
2.97 0.10
0.12
0.75 0.40
0.03
0.25 0.62
0.01
0.1 (0.1)
1.01 0.33
0.04
0.61 0.44
0.03
0.04 0.84
< 0.01
2.09 0.16
0.09
2.26 0.15
0.09
4.7 (1.7) -1.0 (2.0) 3.6 (1.1) 0.5 (1.2) 3.2 (0.8) 1.9 (0.9)
4.39 0.05
0.17
3.27 0.08
0.13
1.07 0.31
0.05
-0.1 (0.1)
0.11 0.74
< 0.01
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Mean (SD)
Post3m - Baseline
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Distal
Postimmediate - Baseline
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Proximal
Baseline
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FMA-UE Total*
Group
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Outcome
-0.1 (0.1) 0.1 (0.1) -0.1 (0.1) -0.2 (0.1) -0.5 (0.2) 5.0 (3.0) 0.5 (3.4) -0.3 (0.7) -0.7 (0.8)
3.66 0.07
0.14
2.06 0.17
0.09
0.96 0.34
0.04
0.13 0.72
0.01
-0.1 (0.2) 0.1 (0.1) -0.1 (0.1) -0.1 (0.2) -0.1 (0.2) 0.7 (0.6) -0.7 (0.7) 0.0 (0.3)
F
p
Partial η2
0.8 (0.4)
ARAT = Action research arm test; BI = Barthel index; FMA-UE = Fugl-Meyer Assessment, upper extremity subscale; MAS = modified Ashworth scale Main analyses use ANCOVA with baseline score as covariate. *Significant baseline differences between groups (p < 0.05)
ACCEPTED MANUSCRIPT Table 3. The number needed to treat of each primary outcome measure. Outcome
Improvements gained
Event rate
ARR (95%CI)
NNT (95% CI)
Control tDCS-SM (baseline n (baseline Control tDCS-SM = 11) n=14) FMA-UE Total
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Post-intervention 5
0.18
0.36
0.18 (-0.16, 0.51)
6 (1.9 - ∞)
Proximal Distal MAS Elbow flexor
2 1
8 8
0.18 0.09
0.57 0.57
0.39 (0.04, 0.73) 0.48 (0.17, 0.79)
3 (1.4, 22.5) 3 (1.3, 5.9)
9
11
0.82
0.79
0.03 (-0.28, 0.35)
31 (3.6 - ∞)
Wrist flexor Finger flexor
11 10
13 14
1.00 0.91
0.93 1.00
0.07 (-0.06, 0.21) 0.09 (-0.08, 0.26)
14 (15.8 - ∞) 11 (3.6 - ∞)
31 (3.6 - ∞) 5 (1.7 - ∞)
Distal MAS Elbow flexor Wrist flexor
5
7
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2
0.45
0.50
0.05 (-0.35, 0.44)
22 (2.3 - ∞)
10 10
10 13
0.91 0.91
0.71 0.93
0.19 (-0.10, 0.49) 0.02 (-0.20, 0.24)
6 (10.4 - ∞) 52 (4.2 - ∞)
Finger flexor
9
9
0.82
0.64
0.18 (-0.16, 0.51)
6 (6.1 - ∞)
3 months follow-up 9 2
11 6
0.82 0.18
0.79 0.43
0.03 (-0.28, 0.35) 0.25 (-0.10, 0.59)
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FMA-UE Total Proximal
FMA-UE Total
EP
6 months follow-up
0
3
0.00
0.21
0.21 (-0.07, 0.43)
5 (2.3 - ∞)
3 4
6 3
0.27 0.36
0.43 0.21
0.16 (-0.21, 0.53) 0.15 (-0.21, 0.51)
7 (1.9 - ∞) 7 (4.8 - ∞)
10 8
10 11
0.91 0.73
0.71 0.79
0.19 (-0.10, 0.49) 0.06 (-0.28, 0.40)
6 (10.4 - ∞) 18 (2.5 - ∞)
Finger flexor
8
14
0.73
1.00
0.27 (0.01, 0.54)
4 (1.9, 104.8)
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Proximal Distal MAS Elbow flexor Wrist flexor
ARR = Absolute Risk Reduction; FMA-UE = Fugl-Meyer Assessment, upper extremity subscale; MAS = modified Ashworth scale; NNT = Number Needed to Treat
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