Neurorehabilitation and Neural Repair

http://nnr.sagepub.com/ Effects of Treatment Intensity in Upper Limb Robot-Assisted Therapy for Chronic Stroke : A Pilot Randomized Controlled Trial
Yu-wei Hsieh, Ching-yi Wu, Wan-wen Liao, Keh-chung Lin, Kuen-yuh Wu and Chia-yi Lee Neurorehabil Neural Repair 2011 25: 503 originally published online 24 March 2011 DOI: 10.1177/1545968310394871 The online version of this article can be found at: http://nnr.sagepub.com/content/25/6/503

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25610.1177/1545968310394871Hsieh et alNeurorehabilitation and Neural Repair The Author(s) 2011 Reprints and permission: http://www. sagepub.com/journalsPermissions.nav

Research Articles

Effects of Treatment Intensity in Upper Limb Robot-Assisted Therapy for Chronic Stroke: A Pilot Randomized Controlled Trial

Neurorehabilitation and Neural Repair 25(6) 503511 The Author(s) 2011 Reprints and permission: http://www. sagepub.com/journalsPermissions.nav DOI: 10.1177/1545968310394871 http://nnr.sagepub.com

Yu-wei Hsieh, MS1, Ching-yi Wu, ScD2, Wan-wen Liao, MS1, Keh-chung Lin, ScD1, 3, Kuen-yuh Wu, PhD1, and Chia-yi Lee, MS4

Abstract Background and Objectives. Robot-assisted therapy (RT) is a current promising intervention in stroke rehabilitation, but more research is warranted for examining its efficacy and the dosebenefit relation. The authors investigated the effects of higher intensity versus lower intensity RT on movements of forearm pronationsupination and wrist flexionextension relative to conventional rehabilitation (CR) in patients poststroke for a mean of 21 months. Methods. In this pilot study, 18 patients with initial mean Fugl-Meyer Assessment (FMA) of 37 to 44 for the upper extremity were randomized to higher intensity RT, lower intensity RT, or CR intervention for 4 weeks. The dose of the higher intensity RT was twice the number of repetitions in the lower intensity RT. Outcome measures at pretreatment and posttreatment were administered to patients to evaluate beneficial and adverse effects of interventions. Primary outcomes were the FMA and Medical Research Council scale. Results. There were significant differences in motor function (P = .04) and daily performance (P = .03) among the 3 groups. The higher intensity RT group showed better improvement in motor function, muscle strength, performance of daily activities, and bimanual ability than the other 2 groups. The intensive RT intervention did not induce higher levels of an oxidative DNA biomarker. Conclusions. Higher intensity of RT that assists forearm and wrist movements may lead to greater improvement in motor ability and functional performance in stroke patients. A sample size of only 20 to 25 in each arm of a larger randomized controlled trial is needed to confirm the findings for similar subjects. Keywords robotics, rehabilitation, comparative efficacy research, treatment dosage, intensity, oxidative stress

Introduction
Stroke remains a leading cause of permanent disability and is a large source of disease burden worldwide.1,2 Robotassisted therapy (RT) for upper extremity (UE) motor function has emerged as a possible adjunct for stroke rehabilitation, although not yet convincingly shown to be better than the same intensity of conventional focused UE therapy.3-9 RT incorporates some therapeutic elements for success in stroke motor rehabilitation into its design: intensive, repetitiveness, feedback, and bilateral training.5-9 Along with these advantages, patients can be trained much more often, which has been shown to lead to better outcomes and have potential to enhance motor learning (eg, the Assisted Rehabilitation and Measurement Guide).10,11 Previous RT studies showed significant, if modest, improvement in UE motor function, strength, and motor control parameters in stroke patients after interventions.5,6,8 Systematic reviews

found that RT significantly improved arm motor function for stroke patients but did not significantly improve daily functions.12,13 Robotics can also provide quantitative control and measurement of therapy (eg, velocity, kinematics, resistance, and range of motion), allowing for research into the treatment dosage of rehabilitation.14 Despite growing empirical evidence for the use of RT in stroke rehabilitation, rigorous research is needed to answer more specific questions that will maximize the benefits from the treatment.15 For example, what is the optimal intensity of RT? What are
1 2

National Taiwan University, Taipei, Taiwan Chang Gung University, Taoyuan, Taiwan 3 National Taiwan University Hospital, Taipei, Taiwan 4 Cathay General Hospital, Taipei, Taiwan Corresponding Author: Keh-chung Lin, ScD, School of Occupational Therapy, College of Medicine, National Taiwan University, 17, F4, Xu Zhou Road, Taipei 100, Taiwan Email: kehchunglin@ntu.edu.tw

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504 the relative beneficial and adverse effects of RT compared with other treatments? Dosage in stroke rehabilitation trials usually uses the duration-based measure of therapy and provides the information regarding the amount of minutes or days per week of therapy provided.16 Most RT trials have offered the treatment in sessions lasting 30 minutes to 1.5 hours, with 3 to 5 sessions per week for 3 to 8 weeks.5,6,8,9 In the EXCITE trial for constraint-induced therapy, the training involved forcing the patient to use the affected arm for up to 6 hours daily for 10 weekdays, and the less-affected hand was placed in a mitt for a goal of 90% of the patients waking hours for 14 days during a 2-week period.17 In addition, one study found that in a standard rehabilitation session, the average of repetitions of the functional UE practice was 32.16 According to recent research, performing about 300 repetitions of taskspecific UE training per session was feasible in stroke rehabilitation.18 Although greater duration or intensity of rehabilitation resulted in more functional improvement,19-21 current data do not allow for a prescription of how much treatment is enough to induce improvements and not harm the patient. Thus, the definition of treatment intensity as the number of movement repetitions per unit of time22 was adopted in this study and was investigated to inform the optimal dosage for further stroke rehabilitation. Moreover, it is important to select the appropriate intensity of exercise or treatment, because exercise that is too intensive can be hazardous.23 The study found that highintensity exercise (ie, 75% maximum oxygen consumption reached) increased oxidative stress in healthy men.23 During prolonged heavy exercise, antioxidant systems may be overwhelmed by excessive reactive oxygen species, leading to cell and tissue damage.24 Stroke patients commonly showed activity intolerance and significantly lower maximal workloads than controls during exercise.25 For healthy people, the RT protocols proposed in this study seem not to have been so stressful or reach the effort level of the previous study where increased oxidative stress was found.23 For stroke patients, however, the same intensity or amount of training may have different impacts from healthy people. In addition, the oxidative stress level has been reported to be higher in acute stroke patients than in control subjects, but the effects of training on oxidative damage have not been addressed in these studies.26,27 To date, the threshold level of training intensity that may cause oxidative stress in stroke patients remains unclear and warrants scrutiny. To address this gap in doseresponse relations in stroke motor rehabilitation, this study investigated the effects of intensive RT on the 8-hydroxy-2-deoxyguanosine (8-OHdG) level, an oxidative DNA biomarker, in stroke patients. Our goals in this study were to (a) investigate the treatment effects of RT on different outcomes relative to conventional rehabilitation (CR) in patients with stroke, (b) test the dose response relations by using 2 groups receiving higher

Neurorehabilitation and Neural Repair 25(6)

Assessed for eligibility (n = 125)

Excluded (n = 107) Did not meet inclusion criteria (n = 93) Refused to participate (n = 14)

Underwent randomization after screening (n = 18)

Assigned to higher intensity RT (n = 6)

Assigned to lower intensity RT (n = 6)

Assigned to conventional rehabilitation (n = 6)

Completed study and analyzed (n = 6)

Completed study and analyzed (n = 6)

Completed study and analyzed (n = 6)

Figure 1. Flow diagram of study participants

Abbreviation: RT, robot-assisted therapy.

intensity and lower intensity RT, and (c) examine the effects of RT training on 8-OHdG, a biomarker of oxidative stress.

Methods Participants
This pilot study recruited 18 patients between August 2009 and May 2010 from the Departments of Physical Medicine and Rehabilitation of 3 medical centers in Taiwan. The study enrolled 14.4% of screened patients (Figure 1). The inclusion criteria were (a) more than 6 months since a unilateral stroke; (b) an initial UE subsection of the FuglMeyer Assessment score of 30 to 56, indicating moderate to mild motor impairment;28,29 (c) no excessive spasticity in elbow and wrist joints of the affected UE (Modified Ashworth Scale <3); (d) ability to follow study instructions and perform study tasks (Mini-Mental Status Examination 24); (e) no upper limb fracture within 3 months; (f) no participation in any experimental rehabilitation or drug studies during the study period; and (g) willing to provide written informed consent. The exclusion criteria were (a) painful arthritis of the elbow, wrist, or finger joints; (b) severe neuropsychologic impairments (eg, global aphasia and severe attention deficits); (c) physician-determined major medical problems or poor physical condition that

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Hsieh et al would interfere with participation; and (d) cerebellar or brain stem lesions to limit potential interference of other symptoms or signs with task accomplishment (eg, ataxia). The institutional review boards of the 3 participating hospitals approved the study, and all patients signed an informed consent document.

505

Study Design and Procedures

A single-blind randomized controlled trial with pretest and posttest assessments was applied in this study. An intentionto-treat analysis was used. The eligible participants were randomly assigned to receive the higher intensity RT, lower intensity RT, or CR according to a 1:1:1 ratio using a random number table. When a new eligible patient was registered, the sealed opaque envelope identifying the group of each participant was given to the therapists, and they were informed of the group allocation to deliver therapy accordingly. At pretreatment and immediately after the intervention, all clinical measures were administered to the patients by the same blinded rater. Before the administration of the clinical measures, the blinded rater was trained to properly administer these measures. This training included careful examination of written instructions and repeated practice. Rater competence was assessed by a senior certified occupational therapist.

Interventions
Patients received higher intensity RT, lower intensity RT, or CR intervention for 20 training sessions (90-105 min/d, 5 d/wk for 4 weeks). Licensed occupational therapists trained in study procedures provided the treatments. All patients otherwise received routine interdisciplinary stroke rehabilitation. Higher intensity RT protocol. The robot-assisted arm trainer, Bi-Manu-Track (Reha-Stim Co, Berlin, Germany; Figure 2), was used in this study. The Bi-Manu-Track enables the symmetrical practice of 2 movement patterns: forearm pronationsupination and wrist flexionextension.5 Each movement pattern has 3 computer-controlled modes: passivepassive (mode 1), activepassive (mode 2, the unaffected arm actively driving the affected arm), and activeactive (mode 3). The speed of movement, the amount of resistance, and range of movement can be adjusted individually. The patients sat at a height-adjustable table with their elbows bent at 90 and put their forearms in the midposition into an arm trough. A simple computer game (eg, picking up apples) that tracks patient movements was placed in front of the patients to provide instant visual movement feedback and to increase participation. The therapist also provided verbal feedback. Within 1 training session, each patient in the higher intensity RT group practiced 600 to 800 repetitions of mode

Figure 2. The Bi-Manu-Track.

1 for 15 minutes, 600 to 800 repetitions of mode 2 for 15 to 20 minutes, and 150 to 200 repetitions of mode 3 for 5 minutes, respectively, for the forearm and the wrist movements. One repetition indicates 1 movement direction; for example, 1 pronation or 1 supination of the forearm counts as 1 repetition. If the affected arm can actively perform forearm pronationsupination or wrist flexionextension, mode 2 can be adjusted to the affected arm actively driving the unaffected arm (300-400 maximal repetitions) to encourage more active movements of the affected arm. We reduced the number of repetitions of mode 1 into this mode (affected arm actively driving), and thus the total number of repetitions was still the same. Before the RT commenced, 5 to 10 minutes of passive range of motion was provided as a warm-up. After the RT, patients received 15 to 20 minutes of functional activities training to help them transfer the acquired motor ability into daily activities performance. The functional activities were selected by patients and therapists and included opening a can or jar, turning a door knob, carrying heavy objects, writing, picking up a phone for listening, using chopsticks, twisting a towel, turning pages of a book, and so on. Lower intensity RT protocol. Except for the treatment intensity, other training principles and practice parameters

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506 were the same as with the higher intensity RT group. Within 1 training session, patients in this lower intensity RT group practiced 300 to 400 repetitions of mode 1 for 15 minutes, 300 to 400 repetitions of mode 2 for 15 to 20 minutes, and 70 to 100 repetitions of mode 3 for 5 minutes, respectively, for the forearm and the wrist movements. In addition, if the affected arm could actively perform forearm pronation supination or wrist flexionextension, mode 2 could be adjusted to the affected arm actively driving the unaffected arm (150-200 maximal repetitions) to encourage more active movements of the affected arm. The dosage of the higher intensity and lower intensity RT groups was determined from findings of animal studies, previous research on the Bi-Manu-Track, and practical concerns. Data from 2 animal studies showed that performing about 400 to 600 repetitions of upper limb tasks per session during motor skill learning induced neural plastic changes.30,31 Furthermore, 200 to 500 repetitions per session for mode 1 and mode 2 were used in prior studies of the Bi-ManuTrack5,32 in which positive benefits of therapy were found. This range might be viewed as the lowest limit of dosage for the Bi-Manu-Track training to have positive outcomes based on current evidence. In addition, the speed of movements and patients tolerance were taken into consideration. Therefore, 300 to 400 repetitions of mode 1 and mode 2 for 15 minutes were selected for the low-intensity RT group. A higher dose, 2-fold of the repetitions in the low-intensity RT group, was set as the intensity of the higher intensity RT group. CR protocol. The CR group received a structured protocol using conventional occupational therapy techniques such as neurodevelopmental techniques33 with emphasis on functional tasks and muscle strengthening. The protocol included (a) passive range of motion exercises, stretching of the affected limb, or facilitatory and inhibitory techniques for 15 to 20 minutes; (b) fine motor or dexterity training for 20 minutes; (c) arm exercises or gross motor training for 20 minutes; (d) muscle strengthening of the affected upper limb for 15 to 20 minutes; and (e) activities of daily living or functional tasks training for 15 to 20 minutes. The activities were adapted based on the level of motor impairment and functional needs of individual patients.

Neurorehabilitation and Neural Repair 25(6) the metacarpophalangeal joints was graded by the MRC in this study, and the average MRC score was calculated. The secondary outcomes were the Motor Activity Log (MAL) and the ABILHAND scale. The MAL contains 30 structured interview questions related to information about the patients perceptions regarding the amount of use (AOU) and quality of movement (QOM) of the affected arm to accomplish common daily activities.39 The rating score of each item for AOU and QOM ranges from 0 to 5, and higher scores indicate better performance. The reliability and validity of the MAL have been established.29,40 The 23-item ABILHAND scale was used to measure bimanual ability.41,42 Patients were asked to estimate the difficulty they had in performing these bimanual tasks on a 3-level scale (0 = impossible, 1 = any difficulty, 2 = easy). The Rasch reliability, construct validity, and responsiveness of the ABILHAND have been established in stroke patients.41,42 Urinary 8-OHdG is a stable and integral biomarker of oxidative DNA damage and was used as a safety outcome.43 Urine samples were collected from the patients before and after intervention and stored at 80C. The urinary 8-OHdG levels were analyzed with a highly sensitive and selective method, using isotope-dilution liquid chromatography with tandem mass spectrometry (LC/MS/MS), as previously published by Hu et al.44 On the basis of previous studies that used the LC/MS/MS analytic method, the mean urinary 8-OHdG levels in the control patients have been reported in the range of 4 to 6 ng/mg creatinine.44,45 The general subscale of the Multidimensional Fatigue Symptom Inventory (MFSI)46 was used to measure general fatigue of the patients. It includes 6 items with a total score ranging from 0 (not at all) to 24 (extremely). The interrater reliability, testretest reliability, and convergent validity of the general subscale of the MFSI have been validated in stroke patients.47

Data Analysis
The 2 test for categoric variables and 1-way analysis of variance for continuous variables were used to compare the baseline characteristics of the 3 groups. Analyses of covariance was used to evaluate treatment efficacy, with pretreatment scores of each outcome measures as the respective covariates, group as the between-subjects factor, and posttreatment scores of each outcome variable as the dependent variables. The Tukey method was used for post hoc pairwise comparisons. The effect size of partial 2 was calculated for each outcome variable to index the magnitude of the performance difference between the 3 groups. A large effect is represented by a partial 2 of at least .138, a moderate effect by .059, and a small effect by .010.48 Statistical analyses were performed with SPSS version 15.0 and SAS version 9.1.3 software (IBM, Somers, New York; SAS Institute, Cary, North Carolina). Values of P < .05 were considered statistically significant.

Outcome Measures
Outcome measures to evaluate preliminary benefits and potential adverse effects were administered to patients before and after treatment. The UE subscale of the FuglMeyer Assessment (FMA) and the Medical Research Council (MRC) scale were used as the primary outcomes. The 33 UE items of the FMA assess the movements and reflexes of the shoulder/elbow/forearm, wrist, hand, and coordination and speed.34-36 Muscle strength of the affected arm was examined by the MRC scale.37,38 The muscle strength of shoulder flexors/abductors, elbow flexors/ extensors, wrist flexors/extensors, and flexors/extensors of

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Hsieh et al
Table 1. Baseline Characteristics of the Study Participants (N = 18) RT Groups Characteristicsa Age, y Gender Male Female Side of stroke Right Left Stroke type Hemorrhagic Ischemic Months after stroke MMSE score MAS score FMA score MRC score Higher Intensity (n = 6) 56.04 (13.74) 4 2 4 2 1 5 21.33 (7.17) 27.33 (2.50) 0.67 (0.16) 44.00 (8.17) 3.40 (0.53) Lower Intensity (n = 6) 52.45 (1.98) 4 2 2 4 0 6 13.00 (7.04) 27.33 (3.20) 0.57 (0.07) 37.67 (10.00) 3.04 (0.64) CR Group (n = 6) 54.00 (8.05) 5 1 .41 2 4 .30 2 4 28.33 (19.9) 28.67 (0.52) 0.66 (0.37) 37.50 (11.69) 3.23 (0.70) P Valueb .86 .76

507

.15 .54 .72 .46 .63

Abbreviations: CR, conventional rehabilitation; FMA, Fugl-Meyer Assessment; MAS, Modified Ashworth Scale; MMSE, Mini-Mental State Examination; MRC, Medical Research Council; RT, robot-assisted therapy. a Continuous data are expressed as mean (standard deviation), categoric data as number. b P values are associated with the 2 test for categoric variables and 1-way analysis of variance for continuous variables.

Results
Eighteen patients (13 men and 5 women) completed the study. Their age range was 31 to 69 years, stroke onset was 6 to 63 months prior, and there were 8 right and 10 left hemisphere lesions (Table 1). The baseline demographic and clinical characteristics of the participants among the 3 groups were not significantly different (Table 1). Most patients showed improvements on primary outcomes after the interventions (Figure 3). Table 2 reports the descriptive and inferential statistics for each outcome of the 3 groups. For the primary outcomes, there was a significant difference in UE motor ability measured by the FMA among the 3 groups (P = .04, partial 2 = .38). Post hoc analyses revealed that the higher intensity RT group showed significantly better improvements in motor ability than the lower intensity RT group (P = .04). The difference in FMA improvements in the lower intensity RT and the CR groups was not significant (P = .88). Moreover, differences in muscle strength measured by the MRC among the 3 groups approached significance (P = .06, partial 2 = .33). The higher intensity RT group showed the most improvement in muscle strength, whereas the CR group showed the least improvement. For the secondary outcomes, a significant difference in the MAL-QOM (ie, quality of movement during daily activities) among the 3 groups was observed (P = .03, partial 2 = .40). Post hoc analyses showed that the higher intensity RT group had significantly larger improvements in the MAL-QOM than the CR group (P = .02). In addition,

although the between-group differences were not significant in the MAL-AOU and ABILHAND, large effects were found (partial 2 = .18 and .25). To sum up, there is a trend that the mean improvement scores from baseline to posttreatment in the higher intensity RT group on the primary and secondary outcomes are higher than those in the lower intensity RT group and the CR group. For the safety outcomes of 8-OHdG and MFSI, there were no significant differences among the 3 groups, and the before-to-after effects were small (Table 2). No treatmentrelated serious adverse events were reported. Most participant ratings of fatigue were low. According to the average score, the lower intensity RT group reported decreased fatigue (pre = 4.83; post = 3.17), and the higher intensity RT (pre = 2.50; post = 3.33) and CR groups (pre = 1.83; post = 2.50) showed slightly increased fatigue after intervention. Urine samples were collected in 10 patients in the RT groups. The 8-OHdG level in most patients decreased or showed nearly no change after treatment. The mean changes of the 2 groups showed decreased 8-OHdG levels after treatment (1.42 and 0.48 ng/mg creatinine), indicating that the intensive RT training did not cause oxidative damage to the patients.

Discussion
Most patients demonstrated improvement in motor ability and functional performance after treatment. Patients in the higher intensity RT group had better outcomes than those in the lower intensity RT group and the CR group on UE motor

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508 A
5

Neurorehabilitation and Neural Repair 25(6) B

10

4 Number of patients Number of patients

0 0 2 4 6 8 FMA change score

0 0.20 0.00 0.20 0.40 0.60 0.80 1.00 MRC change score

Figure 3. The change scores of all patients on the primary outcomes after treatment are shown for the (A) Fugl-Meyer Assessment (FMA) and (B) the Medical Research Council (MRC) scale. Table 2. Descriptive and Inferential Statistics for Each Outcome Measure From Baseline to Posttreatment Baseline Score, Mean (SD) Outcome FMA MRC MAL-AOU MAL-QOM ABILHAND MFSIa 8-OHdGa,b Higher Intensity RT 44.00 (8.17) 3.40 (0.53) 0.68 (0.56) 0.76 (0.50) 0.97 (0.20) 2.50 (2.81) 4.41 (1.88) Lower Intensity RT CR Posttreatment Score, Mean (SD) Higher Intensity RT 49.33 (8.34) 3.81 (0.55) 1.08 (0.72) 1.39 (0.82) 1.22 (0.29) 3.33 (2.16) 2.99 (1.26) Lower Intensity RT CR F 4.28 3.37 1.55 4.67 2.38 0.28 0.38b ANCOVA P .04 .06 .25 .03 .13 .76 .56 Partial 2 .38 .33 .18 .40 .25 .04 .05

37.67 (10.00) 37.50 (11.67) 3.04 (0.64) 3.23 (0.70) 0.26 (0.28) 0.78 (1.16) 0.36 (0.42) 0.80 (1.14) 0.83 (0.22) 0.86 (0.53) 4.83 (5.46) 1.83 (2.86) 3.48 (3.13)

40.00 (10.47) 40.33 (11.86) 3.25 (0.50) 3.33 (0.69) 0.50 (0.60) 0.88 (1.30) 0.62 (0.77) 0.95 (1.25) 0.83 (0.32) 0.92 (0.38) 3.17 (4.54) 2.50 (1.64) 3.00 (2.69)

Abbreviations: 8-OHdG, 8-hydroxy-2-deoxyguanosine; ANCOVA, analysis of covariance; AOU, amount of use; CR, conventional rehabilitation; FMA, Fugl-Meyer Assessment; MAL, Motor Activity Log; MFSI, Multidimensional Fatigue Symptom Inventory; MRC, Medical Research Council; QOM, quality of movement; RT, robot-assisted therapy. a On these measures, lower scores indicate better function. b The 8-OHdG test was only conducted in the higher-intensity and lower-intensity RT groups.

function, muscle strength, performance of daily function, and bimanual ability. Compared with the CR group, the lower intensity RT group performed better on the MRC and the MAL. The lower intensity RT and the CR groups had a similar degree of changes in the FMA and the ABILHAND. Furthermore, the higher intensity RT intervention seemed not to induce deleterious effects of oxidative stress. These interventions, then, can be tolerated by chronic stroke patients with moderate to mild motor deficits. In agreement with one previous trial that used the Bi-Manu-Track,5 the RT protocols used in our study led to greater improvement in UE motor function and muscle strength than the control intervention. In addition, there were 5.3-point gains on the FMA after the higher intensity

RT intervention (within-group, although the FMA at baseline was higher than the other groups) and a mean difference of 3 points on the FMA between the higher intensity RT group and the other 2 groups (between-group). The amount of the difference on the FMA reached what some consider to be the level of minimal clinically meaningful.49 More improvement in muscle strength after the RT than the CR intervention was also observed. The Bi-Manu-Track provided adjustable resistance and principles of progressive resistance exercise was incorporated into treatment, which may contribute to the improved muscle power after RT. However, our beneficial effects of RT on motor function did not corroborate the findings of 2 studies using the MITMANUS.7,9 The differential results may be attributable to

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Hsieh et al differences in motor severity of patients, sample size of studies, and the use of unilateral versus bilateral robotic devices. Unilateral and bilateral interventions for the UE may have different mechanisms of neuroplastic changes even though the degree of motor improvement was similar.50 No significant differences in functional or disability outcomes between the RT and control groups have been reported in some previous studies in which they did not provide additional functional training in the experimental RT groups.8,9 In contrast to previous studies, this study combined functional training (15-20 minutes for each session) with the RT, which may have helped patients to transfer the acquired motor ability and strength into the use of the affected UE in daily activities and thus gain improvements in the MALQOM. Compared with the EXCITE trials criteria for clinically meaningful changes on the MAL-QOM (a score of 3 after treatment),17,29 the data in our study did not reach clinically important changes. However, when using another criterion in which 10% of the score (ie, 0.5 points) was set as minimal clinically important,51 0.63-point gains on the MAL-QOM in the higher intensity RT group can be viewed as clinically relevant. In addition, MAL scores were low in our patients with mild to moderate motor deficits. The primary reason might be that many stroke patients developed learned nonuse of their affected UE, resulting in a discrepancy between what stroke patients can do and how much they actually do.52-54 Further studies should emphasize the actual use of the affected UE in daily activities as home programs and incorporate the use of accelerometers to evaluate the real-world performance of patients. We investigated not only the positive benefits but also potential adverse effects of the intensive RT intervention. Our pilot results showed that the urinary 8-OHdG levels of the patients were not significantly changed and tended to be decreased after RT, indicating the regular RT protocols of this study may be appropriate to patients with chronic UE paresis without inducing oxidative stress. Some previous studies showed an increased 8-OHdG level after heavy or extreme exercise (ie, exercise capacity had 75% maximal oxygen consumption or long-distance running),23,55 whereas some demonstrated no change in 8-OHdG level after exercise (ie, a short-distance triathlon or progressive resistance training).56,57 The discrepant effects of exercise on oxidative stress may be partly due to the type and intensity of exercise studied and the patients studied. Because the 2 RT protocols for UE training used in this study were likely to be modest in intensity, the 8-OHdG levels had no significant change after RT. The 8-OHdG appears to be a promising biomarker of oxidative stress, but more studies are needed to clarify its responsiveness to intensive rehabilitation interventions in stroke patients.58 Furthermore, translating the dosages of high-intensity training from animal models to patients with stroke to balance the efficacy and safety issues of novel

509 treatments in doesresponse studies is critical in furthering neurorehabilitation research. Some limitations of this study should be mentioned. First, this study is a pilot trial with a sample representing a small percentage of all stroke patients, which limits the generalization of the findings. The positive preliminary results do provide a justification for conducting a larger trial. According to the findings of this study and a previous study5 on motor function, the effect size f ranged from 0.40 to 0.78. An estimate of sample size requirements for each group in a 3-group study design given a power of 0.80, and a 2-sided type I error of 0.05 was in a range of 7 to 21 patients. A future efficacy trial should consider recruiting 20 to 25 patients for each group for interventions of at least 4 weeks. Second, the outcome assessments were administered immediately after the intervention. Further studies should include later follow-up for retention. Third, this study did not precisely measure the intensity of the CR group. Further studies have to define the number of repetitions in the activity-based treatment programs per session16,18 and provide the intensity of the CR for comparison with the RT. In addition, although this small study randomized subjects, the higher intensity RT group had higher baseline FMA and MRC scores, which may have biased the outcomes. Further larger studies may use stratified randomization based on motor impairment levels of patients to avoid potential selection bias. The preliminary results showed promise for continued study of the specific effects of RT and investigation of doseresponse relations. Authors Note
Yu-wei Hsieh and Ching-yi Wu have contributed equally to this work.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interests with respect to the authorship and/or publication of this article.

Funding
The author(s) disclosed receipt of the following financial support for the research and/or authorship of this article: This project was supported in part by the National Health Research Institutes (NHRIEX99-9920PI and NHRI-EX99-9742PI) and the National Sciences Council (NSC 96-2628-B-002-033-MY2, NSC 97-2314-B-002008-MY3, and NSC 97-2314-B-182-004- MY3) in Taiwan.

References
1. Muntner P, Garrett E, Klag MJ, Coresh J. Trends in stroke prevalence between 1973 and 1991 in the US population 25 to 74 years of age. Stroke. 2002;33:1209-1213. 2. Dobkin BH. Rehabilitation after stroke. N Engl J Med. 2005;352:1677-1684. 3. Krebs HI, Hogan N. Therapeutic robotics: a technology push: stroke rehabilitation is being aided by robots that guide movement

Downloaded from nnr.sagepub.com at University of Maryland Baltimore Health Sci & Hum Serv Lib on April 9, 2012

510
of shoulders and elbows, wrists, hands, arms and ankles to significantly improve recovery of patients. Proc IEEE Inst Electr Electron Eng. 2006;94:1727-1738. Housman SJ, Scott KM, Reinkensmeyer DJ. A randomized controlled trial of gravity-supported, computer-enhanced arm exercise for individuals after stroke. Neurorehabil Neural Repair. 2009;23:505-514. Hesse S, Werner C, Pohl M, Rueckriem S, Mehrholz J, Lingnau ML. Computerized arm training improves the motor control of the severely affected arm after stroke: a single-blinded randomized trial in two centers. Stroke. 2005;36:1960-1966. Kahn LE, Zygman ML, Rymer WZ, Reinkensmeyer DJ. Robot-assisted reaching exercise promotes arm movement recovery in chronic hemiparetic stroke: a randomized controlled pilot study. J Neuroeng Rehabil. 2006;3:12. Lo AC, Guarino PD, Richards LG, et al. Robot-assisted therapy for long-term upper-limb impairment after stroke. N Engl J Med. 2010;362:1772-1783. Lum PS, Burgar CG, Shor PC, Majmundar M, Van der Loos M. Robot-assisted movement training compared with conventional therapy techniques for the rehabilitation of upperlimb motor function after stroke. Arch Phys Med Rehabil. 2002;83:952-959. Volpe BT, Lynch D, Rykman-Berland A, et al. Intensive sensorimotor arm training mediated by therapist or robot improves hemiparesis in patients with chronic stroke. Neurorehabil Neural Repair. 2008;22:305-310. Fischer H, Kahn LE, Pelosin E, et al. Can robot-assisted therapy promote generalization of motor learning following stroke? Preliminary results. Paper presented at: First IEEE/ RAS-EMBS International Conference on Biomedical Robotics and Biomechatronics; 2006; Pisa, Italy. Timmermans AA, Seelen HA, Willmann RD, Kingma H. Technology-assisted training of arm-hand skills in stroke: concepts on reacquisition of motor control and therapist guidelines for rehabilitation technology design. J Neuroeng Rehabil. 2009;6:1. Kwakkel G, Kollen BJ, Krebs HI. Effects of robot-assisted therapy on upper limb recovery after stroke: a systematic review. Neurorehabil Neural Repair. 2008;22:111-121. Mehrholz J, Platz T, Kugler J, Pohl M. Electromechanical and robot-assisted arm training for improving arm function and activities of daily living after stroke. Stroke. 2009;40:e392-e393. Boesecker C, Dipetro L, Volpe B, Krebs HI. Kinematic robotbased evaluation scales and clinical counterparts to measure upper limb performance in patients with chronic stroke. Neurorehabil Neural Repair. 2010;24:62-69. Whitall J. Stroke rehabilitation research: time to answer more specific questions? Neurorehabil Neural Repair. 2004;18:3-8. Lang CE, Macdonald JR, Reisman DS, et al. Observation of amounts of movement practice provided during stroke rehabilitation. Arch Phys Med Rehabil. 2009;90:1692-1698. Wolf SL, Winstein CJ, Miller JP, et al. Effect of constraintinduced movement therapy on upper extremity function 3 to

Neurorehabilitation and Neural Repair 25(6)

9 months after stroke: the EXCITE randomized clinical trial. JAMA. 2006;296:2095-2104. 18. Birkenmeier RL, Prager EM, Lang CE. Translating animal doses of task-specific training to people with chronic stroke in 1-hour therapy sessions: a proof-of-concept study. Neurorehabil Neural Repair. 2010;24:620-635. 19. Byl NN, Pitsch EA, Abrams GM. Functional outcomes can vary by dose: learning-based sensorimotor training for patients poststroke. Neurorehabil Neural Repair. 2008; 22:494-504. 20. Kwakkel G, van Peppen R, Wagenaar RC, et al. Effects of augmented exercise therapy time after stroke: a meta-analysis. Stroke. 2004;35:2529-2539. 21. Winstein CJ, Rose DK, Tan SM, Lewthwaite R, Chui HC, Azen SP. A randomized controlled comparison of upperextremity rehabilitation strategies in acute stroke: a pilot study of immediate and long-term outcomes. Arch Phys Med Rehabil. 2004;85:620-628. 22. Dromerick AW, Lum PS, Hidler J. Activity-based therapies. NeuroRx. 2006;3:428-438. 23. Goto C, Higashi Y, Kimura M, et al. Effect of different intensities of exercise on endothelium-dependent vasodilation in humans: role of endothelium-dependent nitric oxide and oxidative stress. Circulation. 2003;108:530-535. 24. Banerjee AK, Mandal A, Chanda D, Chakraborti S. Oxidant, antioxidant and physical exercise. Mol Cell Biochem. 2003;253:307-312. 25. Gordon NF, Gulanick M, Costa F, et al. Physical activity and exercise recommendations for stroke survivors: an American Heart Association scientific statement from the Council on Clinical Cardiology, Subcommittee on Exercise, Cardiac Rehabilitation, and Prevention; the Council on Cardiovascular Nursing; the Council on Nutrition, Physical Activity, and Metabolism; and the Stroke Council. Stroke. 2004;35:1230-1240. 26. El Kossi MM, Zakhary MM. Oxidative stress in the context of acute cerebrovascular stroke. Stroke. 2000;31:1889-1892. 27. Mizukoshi G, Katsura K, Katayama Y. Urinary 8-hydroxy2-deoxyguanosine and serum s100 in acute cardioembolic stroke patients. Neurol Res. 2005;27:644-646. 28. Daly JJ, Hogan N, Perepezko EM, et al. Response to upperlimb robotics and functional neuromuscular stimulation following stroke. J Rehabil Res Dev. 2005;42:723-736. 29. Park SW, Wolf SL, Blanton S, Winstein C, Nichols-Larsen DS. The EXCITE trial: predicting a clinically meaningful Motor Activity Log outcome. Neurorehabil Neural Repair. 2008;22:486-493. 30. Kleim JA, Barbay S, Nudo RJ. Functional reorganization of the rat motor cortex following motor skill learning. J Neurophysiol. 1998;80:3321-3325. 31. Nudo RJ, Milliken GW, Jenkins WM, Merzenich MM. Usedependent alterations of movement representations in primary motor cortex of adult squirrel monkeys. J Neurosci. 1996;16:785-807. 32. Hesse S, Schulte-Tigges G, Konrad M, Bardeleben A, Werner C. Robot-assisted arm trainer for the passive and active practice

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15. 16.

17.

Downloaded from nnr.sagepub.com at University of Maryland Baltimore Health Sci & Hum Serv Lib on April 9, 2012

Hsieh et al
of bilateral forearm and wrist movements in hemiparetic subjects. Arch Phys Med Rehabil. 2003;84:915-920. 33. Bobath B. Adult Hemiplegia: Evaluation and Treatment. London, England: Heinemann; 1990. 34. Fugl-Meyer AR, Jaasko L, Leyman I, Olsson S, Steglind S. The post-stroke hemiplegic patient. 1. A method for evaluation of physical performance. Scand J Rehabil Med. 1975;7:13-31. 35. Hseuh IP, Hsu MJ, Sheu CF, Lee S, Hsieh CL, Lin JH. Psychometric comparisons of 2 versions of the Fugl-Meyer Motor Scale. Neurorehabil Neural Repair. 2008;22:737-744. 36. Platz T, Pinkowski C, van Wijck F, Kim IH, di Bella P, Johnson G. Reliability and validity of arm function assessment with standardized guidelines for the Fugl-Meyer Test, Action Research Arm Test and Box and Block Test: a multicentre study. Clin Rehabil. 2005;19:404-411. 37. Medical Research Council. Aids to the Examination of the Peripheral Nervous System. London, England: Her Majestys Stationery Office; 1976. (Memorandum No. 45) 38. Gregson JM, Leathley MJ, Moore AP, Smith TL, Sharma AK, Watkins CL. Reliability of measurements of muscle tone and muscle power in stroke patients. Age Ageing. 2000;29:223-228. 39. Taub E, Miller NE, Novack TA, et al. Technique to improve chronic motor deficit after stroke. Arch Phys Med Rehabil. 1993;74:347-354. 40. van der Lee JH, Beckerman H, Knol DL, de Vet HC, Bouter LM. Clinimetric properties of the Motor Activity Log for the assessment of arm use in hemiparetic patients. Stroke. 2004;35:1410-1414. 41. Penta M, Tesio L, Arnould C, Zancan A, Thonnard JL. The ABILHAND questionnaire as a measure of manual ability in chronic stroke patients: Rasch-based validation and relationship to upper limb impairment. Stroke. 2001;32:1627-1634. 42. Penta M, Thonnard JL, Tesio L. ABILHAND: a Raschbuilt measure of manual ability. Arch Phys Med Rehabil. 1998;79:1038-1042. 43. Mei S, Yao Q, Wu C, Xu G. Determination of urinary 8-hydroxy-2-deoxyguanosine by two approaches-capillary electrophoresis and GC/MS: an assay for in vivo oxidative DNA damage in cancer patients. J Chromatogr B Analyt Technol Biomed Life Sci. 2005;827:83-87. 44. Hu CW, Wu MT, Chao MR, et al. Comparison of analyses of urinary 8-hydroxy-2-deoxyguanosine by isotope-dilution liquid chromatography with electrospray tandem mass spectrometry and by enzyme-linked immunosorbent assay. Rapid Commun Mass Spectrom. 2004;18:505-510.

511
45. Wong RH, Hu CW, Yeh CY, et al. Sulfotransferase 1a1 and glutathione s-transferase p1 genetic polymorphisms modulate the levels of urinary 8-hydroxy-2-deoxyguanosine in betel quid chewers. Arch Toxicol. 2008;82:313-321. 46. Stein KD, Martin SC, Hann DM, Jacobsen PB. A multidimensional measure of fatigue for use with cancer patients. Cancer Pract. 1998;6:143-152. 47. Mead G, Lynch J, Greig C, Young A, Lewis S, Sharpe M. Evaluation of fatigue scales in stroke patients. Stroke. 2007;38:2090-2095. 48. Cohen J. Statistical Power Analysis for the Behavior Sciences. 2nd ed. Hillsdale, NJ: Erlbaum; 1988. 49. Lo AC, Guarino P, Krebs HI, et al. Multicenter randomized trial of robot-assisted rehabilitation for chronic stroke: methods and entry characteristics for VA ROBOTICS. Neurorehabil Neural Repair. 2009;23:775-783. 50. Whitall J, Waller SM, Sorkin JD, et al. Bilateral and unilateral arm training improve motor function through differing neuroplastic mechanisms: a single-blinded randomized controlled trial. Neurorehabil Neural Repair. 2011;25:118-129. 51. van der Lee JH, Wagenaar RC, Lankhorst GJ, Vogelaar TW, Deville WL, Bouter LM. Forced use of the upper extremity in chronic stroke patients: results from a single-blind randomized clinical trial. Stroke. 1999;30:2369-2375. 52. Andrews K, Stewart J. Stroke recovery: he can but does he? Rheumatol Rehabil. 1979;18:43-48. 53. Taub E, Wolf SL. Constraint-induced movement techniques to facilitate upper extremity use in stroke patients. Top Stroke Rehabil. 1997;3:38-61. 54. Uswatte G, Taub E, Morris D, Light K, Thompson PA. The Motor Activity Log-28: assessing daily use of the hemiparetic arm after stroke. Neurology. 2006;67:1189-1194. 55. Poulsen HE, Loft S, Vistisen K. Extreme exercise and oxidative DNA modification. J Sports Sci. 1996;14:343-346. 56. Hartmann A, Pfuhler S, Dennog C, Germadnik D, Pilger A, Speit G. Exercise-induced DNA effects in human leukocytes are not accompanied by increased formation of 8-hydroxy-2deoxyguanosine or induction of micronuclei. Free Radic Biol Med. 1998;24:245-251. 57. Rall LC, Roubenoff R, Meydani SN, Han SN, Meydani M. Urinary 8-hydroxy-2-deoxyguanosine (8-OHdG) as a marker of oxidative stress in rheumatoid arthritis and aging: effect of progressive resistance training. J Nutr Biochem. 2000;11:581-584. 58. Cherubini A, Ruggiero C, Polidori MC, Mecocci P. Potential markers of oxidative stress in stroke. Free Radic Biol Med. 2005;39:841-852.

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