AFTER STROKE, RESIDUAL neurologic impairments

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1 ORIGINAL ARTICLE Cortical Reorganization Induced by Body Weight Supported Treadmill Training in Patients With Hemiparesis of Different Stroke Durations Yea-Ru Yang, PhD, PT, I-Hsuan Chen, BS, PT, Kwong-Kum Liao, MD, Chia-Chi Huang, MS, PT, Ray-Yau Wang, PhD, PT ABSTRACT. Yang Y-R, Chen I-H, Liao K-K, Huang C-C, Wang R-Y. Cortical reorganization induced by body weight supported treadmill training in patients with hemiparesis of different stroke durations. Arch Phys Med Rehabil 2010;91: Objective: To investigate corticomotor changes induced by body weight supported treadmill training (BWSTT) in patients with short or long poststroke duration. Design: Single-blinded and randomized controlled trial. Setting: Neurologic physical therapy research laboratory. Participants: Hemiparesis patients (N 18) whose motorevoked potentials could be induced participated in this study. Subjects in each hemiparesis postonset of short ( 6mo) or long ( 12mo) duration group were randomly assigned to either the control or experimental group. Interventions: Subjects in the experimental groups participated in BWSTT for 4 weeks. Those in the control groups received the general exercise program. Main Outcome Measures: The primary outcomes were motor threshold and map size of the abductor hallucis muscle in the ipsilesional hemisphere. The secondary outcome was Fugl-Meyer Assessment. Outcome measures were blindly assessed before and after completing the 4 weeks of training. Results: The 4-week BWSTT resulted in a decrease of motor threshold and an increase of map size in subjects with hemiparesis of short duration, whereas only the expansion of the map size was noted in subjects with hemiparesis of long duration. Improvement of motor control occurred in subjects with hemiparesis of both short and long duration after BWSTT. Conclusions: The BWSTT results in similar improvement in motor control but different patterns of treatment-induced cortical reorganization in subjects with different poststroke durations. Key Words: Rehabilitation; Stroke by the American Congress of Rehabilitation Medicine AFTER STROKE, RESIDUAL neurologic impairments lead to motor performance difficulty, which results in impaired walking ability. 1 The BWSTT is a repetitive taskspecific approach including motor task and sensory feedback, which are fundamental for treatment-induced cortical reorganization. 2,3 BWSTT consists of using an overhead suspension system and harness to support partial body weight of patients while walking on the treadmill. It has been suggested as an effective way to improve motor and gait performance for patients with stroke in subacute and chronic stages. 4,5 Forrester et al 2 reported that treadmill training for 3 months altered responsiveness of the lower extremity central motor pathways to a short-term treadmill stimulus. Our previous results showed that changes in corticospinal excitability correlated with functional recovery after 12 additional sessions of BWSTT. 3 Contrary to the chronic patients, little information is available on effects of BWSTT regarding the corticospinal system in subacute stroke subjects, not to mention comparisons of such effects in subjects with different poststroke durations. However, studies investigating treatment-induced cortical reorganization after CIMT in stroke subjects with different postonset durations have been noted. In 2 separate studies, Liepert et al 6,7 demonstrated that increased map size with identical motor threshold occurred in both subacute and chronic stroke patients receiving CIMT. On the other hand, Sawaki et al 8 recently reported that map size did not significantly enlarge in subacute stroke after CIMT. The influence of poststroke duration on cortical reorganization in response to treatment is still unclear; however, it is very important for rehabilitation. We hypothesized that a task-specific practice would induce different cortical reorganization patterns between subjects with short stroke duration and those with long stroke duration. Therefore, the purpose of this study was to investigate the effects of poststroke duration on cortical reorganization induced by the BWSTT. METHODS 513 Subjects Subjects with stroke were recruited from a medical center in the Taipei area. The diagnosis, age, sex, stroke type, lesion side, and onset duration of hemiparesis were obtained from patient interviews and medical charts. From the Department of Physical Therapy and Assistive Technology, National Yang-Ming University, Taipei, Taiwan (Yang, Chen, Wang); the Neurological Institute (Liao) and Department of Physical Medicine and Rehabilitation (Huang), Taipei Veterans General Hospital, Taipei, Taiwan; and Department of Education and Research, Taipei City Hospital, Taipei, Taiwan (Yang, Wang). Supported by the National Health Research Institutes of the Republic of China (grant nos. NHRI-EX EI and NHRI-EX EI). No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit on the authors or on any organization with which the authors are associated. Reprint requests to Ray-Yau Wang, PhD, PT, 155, Sec. 2, Li-Nong St., Beitou District, Taipei, 112, Taiwan, rywang@ym.edu.tw /10/ $36.00/0 doi: /j.apmr AH ANOVA BWS BWSTT CIMT FMA MEP TMS List of Abbreviations abductor hallucis analysis of variance body weight support body weight supported treadmill training constraint-induced movement therapy Fugl-Meyer Assessment motor-evoked potential transcranial magnetic stimulation

2 514 CORTICAL CHANGE AND POSTSTROKE DURATION, Yang Fig 1. Flow diagram of the study. The criteria for subject selection were as follows: (1) diagnosis of unilateral hemiparesis secondary to cerebrovascular accident with postonset duration less than 6 months (short duration group) or more than 12 months (long duration group) 9 and (2) ability to follow simple verbal commands or instructions. The exclusion criteria were (1) unstable medical conditions, (2) history of other diseases known to interfere with participating in the study, (3) past seizure history, (4) cardiac pacemaker, and (5) severe cardiovascular problems. In addition, subjects were excluded if their MEPs of ipsilesional hemisphere could not be induced by TMS. Twenty subjects with short poststroke onset duration and 20 subjects with long poststroke duration were identified as potential participants for this study. As a result, 9 subjects with hemiparesis of short duration and 9 subjects with long duration signed the informed consent and participated in the study. Participants in short and long duration groups were randomly assigned to either control or experimental group by an independent person who selected 1 of the sealed envelopes 30 minutes before beginning the intervention (fig 1). Procedures The study protocol was approved by an institutional human research review board and explained to all included subjects prior to participating in the study. The outcomes including corticomotor activity and motor performance were measured by an assessor who was blinded as to subjects group placement before intervention (pre) and after completing the 4-week training (post). The primary outcome measures were motor threshold and map size. The secondary outcome measure was the FMA. Intervention Subjects in the experimental group received 30-minute BWSTT followed by the 20-minute general exercise program, 3 sessions a week, for a total of 12 sessions. The protocol of

3 CORTICAL CHANGE AND POSTSTROKE DURATION, Yang 515 BWSTT according to our previous study is briefly described. 3 The overhead harness involving a pelvic belt primarily supported the pelvis and lower abdomen. Support of less than 40% of the body weight was provided and decreased to the maximum extent possible. The criterion for determining the amount of BWS was the patient s ability to carry the remaining load on the paretic limb with less than 15 of knee flexion during single-support phase. The amount of BWS determined by the therapist was progressively decreased if the patient s ability increased with training. The treadmill speed was adjusted based on the subject s comfortable walking speed. The treatments were provided by the same 2 physiotherapists. They assisted in correcting patients gait pattern and directed the movement of the pelvis during training. Subjects in the control group received the general exercise program for 50 minutes 3 times a week for a total of 12 sessions. The general exercise program included stretching, strengthening, endurance, and overground walking training. Outcome Measures Corticomotor activity. The motor threshold and map size of AH elicited by TMS were used to indicate the corticomotor activity. 10 The MEPs of AH in the paretic side were recorded by an electromyographic machine a in response to TMS (Magstim 200 electromagnetic stimulation b ) delivered through a figure-of-eight coil placed on the contralateral motor cortex. Evidence from primate studies indicates that spinal motoneurons innervating distal muscles of the lower limb receive more extensive cortical projections from the contralateral motor cortex than proximal muscles. 11 Therefore, we used the activation of AH to indicate the treatment-induced brain reorganization in our study. During the TMS measurement, subjects sat comfortably in a chair with hips and knees in 90 flexion and wearing a fitted cap marked with a coordinate system (distance of 1cm). Subjects were instructed to completely relax their leg during the evaluation period. The coil was positioned parallel with the coronal plane and the handle of the coil pointed outward. The resting motor threshold provides the information about the corticospinal excitability. Motor threshold is determined at rest as the minimum percentage of the stimulation output that elicits MEPs greater than.05mv peak-to-peak amplitude in at least 5 out of 10 consecutive stimuli over the motor cortex. 12 The map size indicates the area of neurons activated. It is expressed as the number of scalp positions with stimulations that evoked MEPs more than.05mv in at least 1 out of 4 consecutive trials. 13 Prior to mapping, the optimal spot to elicit MEPs in the target muscle was determined. At this spot, the motor threshold was assessed. During mapping, the stimulation intensity was applied with 110% of the motor threshold. 14 The coil was moved over the scalp in steps of 1cm with standard procedures to ensure all positions were assessed. 3 Each position was defined in relation to the vertex to be relocated in subsequent mapping procedures. The intensity used in the postassessment was the same as in the preassessment. 3,13 Motor performance. The motor control of lower limb was assessed by the FMA including reflexes, synergistic patterns, and coordination. 15,16 Each item was scored using a 3-point ordinal scale from 0 (no performance) to 2 (complete performance), with a maximum of 34 points. Statistical Analysis All analyses were performed using SPSS version 16.0 statistical software. c Descriptive statistics were generated for all variables, and distributions of the variables were expressed as Table 1: Demographic and Clinical Features of Participants Variables Short Duration Experimental Control Long Duration Experimental Control Participants Sex Men Women Type of stroke Hemorrhage Infarction Affected side Right Left Age (y) Time since stroke (y) NOTE. Values are number or mean SE. means SEs. Intergroup differences among baseline characteristics were evaluated with a 1-way ANOVA or chi-square analysis. A (time duration intervention) repeatedmeasure ANOVA was applied for analysis of primary and secondary outcome variables. Time point (pre- and postintervention) was the within-group factor. Duration (short and long) and intervention (BWSTT and general exercise) were the between-group factors. Statistical significance was set at P less than.05. RESULTS Before intervention, there were no significant differences among groups in all clinical features and measures. All subjects successfully completed the 4-week training program. The detailed clinical features of all participants are presented in table 1. Motor Threshold The results of motor threshold are illustrated in figure 2A. The ANOVA of the motor threshold revealed significant interaction effects on time duration (F 1,14 5.5, P.035) and time intervention (F 1,14 7.6, P.015). No significant interaction effect on time duration intervention was noted. These findings indicate that a decrease of the motor threshold for subjects in the short duration group was more than that in the long duration group, whether they received the BWSTT or the general exercise program. Furthermore, a decrease of the motor threshold in subjects who received the BWSTT was more than that in subjects who received the general exercise program, whether they were in the short or long duration group. There was a significant main effect on time (F 1, , P.004). The post hoc paired t test revealed a significant decrease in the motor threshold after treatment for subjects in the short duration experimental group (from to , P.025), but not in the long duration experimental group (from to ). The motor threshold remained almost unchanged over time for subjects in both short duration control group (from to ) and long duration control group (from to ). Map Size The results of map size are illustrated in figure 2B. A ANOVA of the map size revealed a significant interaction effect on time intervention (F 1,14 9.0, P.009) but

4 516 CORTICAL CHANGE AND POSTSTROKE DURATION, Yang Fig 2. Motor threshold (A) and map size (B) in subjects with short or long poststroke duration. *P<.05 denotes a significant withingroup difference between pre- and postintervention by paired t test. For subjects in the short duration experimental group, there was a significant decrease in the motor threshold and a significant increase in the map size after BWSTT. For subjects in the long duration experimental group, there was a significant increase in the map size after BWSTT. not on time duration. No significant interaction on time duration intervention was noted. These findings indicate that an increase of the map size in subjects receiving the BWSTT was more than that in subjects receiving the general exercise program, whether they were in the short or long duration group. There was a significant main effect on time (F 1, , P.002). The post hoc paired t test revealed a significant increase in the map size after treatment for subjects in both short duration experimental group (from to , P.038) and long duration experimental group (from to , P.018). Example of TMS map area before and after BWSTT in 2 representative subjects is shown in figure 3. However, the map size did not change significantly over time for subjects in both short duration control group (from to ) and long duration control group (from to ). Motor Control The results of FMA are illustrated in figure 4. A2 2 2 ANOVA of the FMA revealed a significant interaction effect on time intervention (F 1, , P.001) but not on time duration. No significant interaction on time duration intervention was noted. These findings indicate that the improvement of the FMA scores in subjects receiving the BWSTT was more than that in subjects receiving the general exercise program, whether they were in the short or long duration group. There was a significant main effect on time (F 1, , P.001). The post hoc paired t tests revealed a significant increase in the FMA scores after treatment for subjects in both short duration experimental group (from to , P.001) and long duration experimental group (from to , P.001). However, the FMA scores remained unchanged over time for subjects in both short duration control group (from to ) and long duration control group (from to ). DISCUSSION This is a randomized controlled trial to investigate the comparisons of different poststroke durations on cortical reorganization induced by BWSTT. In the present study, the 4-week BWSTT resulted in a decrease in the motor threshold and an increase in the motor map size in subjects with hemiparesis of short duration, whereas an expansion of the motor map size but not the changes in the motor threshold were noted in subjects with hemiparesis of long duration. Improvement of lower extremity motor control occurred in subjects with hemiparesis of short and long duration after BWSTT. To our best knowledge, this is the first study using the corticospinal excitability and cortical map to demonstrate the treatment-induced cortical changes in subjects with different postonset durations emphasizing the lower extremity recovery. The map size indicates the area of activated neurons. Increase of motor output map reflects an enlargement of the cortical representation area. The motor threshold is the lowest intensity of the stimulate output. Decreased motor threshold indicates that the neuronal excitability in the center of the representation area was increased. After the BWSTT, an increase of map size with a decrease of motor threshold implied that more neurons were recruited and target muscle was more easily activated through the corticospinal tract in subjects with the short duration of hemiparesis. However, Liepert et al 7 reported an enlargement of the motor map with unchanged motor threshold in subacute stroke subjects after 1-week CIMT to upper extremity. A longitudinal functional magnetic resonance imaging study revealed that in the subacute stage, the early and transient recruitment of supplementary motor area and premotor cortex occurred before reorganization of primary sensorimotor cortex. 17 The 4-week treatment period in our study may have been long enough to result in activation of primary motor cortex in addition to other areas. Put together, these results may indicate that a repetitive task-specific approach, rather than general exercise, can enhance brain reorganization in subjects with relatively short poststroke duration. However, the results of the map size in the short duration group must be interpreted with caution. The intensity used postassessment was the same as in the preassessment. If the patient s motor threshold is decreased after training, the stimulus intensity relative to the baseline threshold increases in the postassessment. Therefore, effects of threshold changes may be conflated with those related to map distribution. In the long duration of hemiparesis, an expansion of the motor map with unchanged motor threshold occurred in subjects receiving the BWSTT. Because the motor threshold determined in the center of an output map remained unchanged, it indicated that additional neural populations adjacent to the former neuronal network were recruited, and the main increases in excitability may occur at the border rather than the center of the representation area. Our previous study also revealed similar results. 3 Furthermore, the improvement of lower extremity control paralleled the increase of map size after BWSTT. It indicated that the recruitment of additional

5 CORTICAL CHANGE AND POSTSTROKE DURATION, Yang 517 Fig 3. Example of motor map area before and after BWSTT in 2 representative subjects. The grid size is 1cm and (0,0) is Cz in the electroencephalogram system. Increased map size was observed in subjects assigned to the BWSTT group regardless of short (top) or long (bottom) duration group. neural populations was the possible strategy rather than increase of corticospinal excitability to enhance motor recovery in patients with hemiparesis of long duration after repetitive task-specific training. According to our results, it is suggested that a decrease of motor threshold induced by the increased excitability of neurons occurred more obviously in subjects with hemiparesis of short duration. However, significantly increased map area due to increased area of neurons activated happened whether in the short or long duration of hemiparesis after BWSTT. Improvement of lower extremity motor control was noted both in subjects with short and long poststroke duration. Together with results of corticomotor activity and motor performance, it implies the role of corticospinal connectivity on the motor control of lower extremity for patients with stroke receiving the BWSTT. CONCLUSIONS The BWSTT results in a similar improvement of motor control but different patterns of treatment-induced cortical reorganization in subjects with hemiparesis of short and long duration. For the subjects with hemiparesis of less than 6 months, the improvement of motor control attributed at least partly to the increased excitability of optimal spot and the amount of cortex devoted to movement representation. For the subjects with hemiparesis over 12 months, the recruitment of cortical representation area instead of the excitability of optimal spot may be one of the dominant cortical reorganization

6 518 CORTICAL CHANGE AND POSTSTROKE DURATION, Yang Fig 4. FMA in subjects with short or long poststroke duration. *P<.05 denoted a significant within-group difference between preand postintervention by paired t test. For subjects in the short and long duration experimental groups, there was a significant improvement in FMA after BWSTT. patterns. Even with the limited subject number, our data provide the first evidence about treadmill-induced lower extremity cortical reorganization in different poststroke durations, especially using parallel groups randomized controlled design to compare subjects receiving the BWSTT with subjects receiving the general exercise program. References 1. Duncan PW. Stroke disability. Phys Ther 1994;74: Forrester LW, Hanley DF, Macko RF. Effects of treadmill exercise on transcranial magnetic stimulation-induced excitability to quadriceps after stroke. Arch Phys Med Rehabil 2006;87: Yen CL, Wang RY, Liao KK, Huang CC, Yang YR. Gait training induced change in corticomotor excitability in patients with chronic stroke. Neurorehabil Neural Repair 2008;22: Werner C, Bardeleben A, Mauritz KH, Kirker S, Hesse S. Treadmill training with partial body weight support and physiotherapy in stroke patients: a preliminary comparison. Eur J Neurol 2002; 9: Trueblood PR. Partial body weight treadmill training in persons with chronic stroke. NeuroRehabilitation 2001;16: Liepert J, Miltner WH, Bauder H, et al. Motor cortex plasticity during constraint-induced movement therapy in stroke patients. Neurosci Lett 1998;250: Liepert J, Uhde I, Graf S, Leidner O, Weiller C. Motor cortex plasticity during forced-use therapy in stroke patients: a preliminary study. J Neurol 2001;248: Sawaki L, Butler AJ, Xiaoyan L, et al. Constraint-induced movement therapy results in increased motor map area in subjects 3 to 9 months after stroke. Neurorehabil Neural Repair 2008;22: Wang RY, Yen L, Lee CC, Lin PY, Wang MF, Yang YR. Effects of an ankle-foot orthosis on balance performance in patients with hemiparesis of different durations. Clin Rehabil 2005;19: Malcolm MP, Triggs WJ, Light KE, et al. Reliability of motor cortex transcranial magnetic stimulation in four muscle representations. Clin Neurophysiol 2006;117: Jankowska E, Padel Y, Tanaka R. Projections of pyramidal tract cells to alpha-motoneurones innervating hind-limb muscles in the monkey. J Physiol 1975;249: Pascual-Leone A, Nguyet D, Cohen LG, Brasil-Neto JP, Cammarota A, Hallett M. Modulation of muscle responses evoked by transcranial magnetic stimulation during the acquisition of new fine motor skills. J Neurophysiol 1995;74: Koski L, Mernar TJ, Dobkin BH. Immediate and long-term changes in corticomotor output in response to rehabilitation: correlation with functional improvements in chronic stroke. Neurorehabil Neural Repair 2004;18: Liepert J, Bauder H, Wolfgang HR, Miltner WH, Taub E, Weiller C. Treatment-induced cortical reorganization after stroke in humans. Stroke 2000;31: 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: Sanford J, Moreland J, Swanson LR, Stratford PW, Gowland C. Reliability of the Fugl-Meyer assessment for testing motor performance in patients following stroke. Phys Ther 1993;73: Tombari D, Loubinoux I, Pariente J, et al. A longitudinal fmri study: in recovering and then in clinically stable sub-cortical stroke patients. Neuroimage 2004;23: Suppliers a. Neuropack 8, Nihon Kohden, Nishiochiai, Shinjuku-ku, Tokyo, Japan. b. Magstim Co Ltd, Spring Gardens, Whitland, Carmarthenshire, Wales, SA34 0HR, UK. c. SPSS Inc, 233 S Wacker Dr, 11th Fl, Chicago, IL