Abstract
Introduction
Stroke is one of the most prevalent neurological conditions worldwide, especially among the elderly. Recovery of function in the hemiparetic upper extremity (UE) is noted in less than 15% of patients after stroke in the case of initial paralysis (Hendricks et al., 2002). It has been reported that the major portion of recovery of UE motor impairment occurs over the first few months (Kwakkel et al., 2006). However, recent newly developed approaches for rehabilitation have also improved UE motor function in patients with chronic stroke (Wolf et al., 2006; Stinear et al., 2008; Fujiwara et al., 2009).
Hybrid assistive neuromuscular dynamic stimulation (HANDS) therapy is a newly developed therapeutic approach that has shown promise in improving UE function in patients with chronic stroke (Fujiwara et al., 2009, 2015; Shindo et al., 2011a). In HANDS therapy, closed-loop, electromyogram-controlled neuromuscular electrical stimulation (NMES) is applied to the paretic finger extensors, combined with the use of a wrist-hand splint, 8 hours a day for 3 weeks. This closed-loop electrical stimulator continually changes its stimulation intensity in direct proportion to the voluntary electromyographic (EMG) amplitude of the paretic finger extensors, and it becomes easier for participants to extend their paretic fingers and perform pinch and release. Participants can therefore use this stimulator at will in their daily lives for as long as 8 hours a day. A randomized control study showed that HANDS therapy in addition to standard rehabilitation produced a significantly greater improvement of paretic UE motor function in patients with severe to moderate hemiparesis, compared with a control group of patients with stroke (Shindo et al., 2011a). However, detection of EMG activity is necessary in order to apply HANDS therapy on paretic finger extensor muscles (e.g., the extensor digitorum communis (EDC) or the extensor pollicis longus (EPL).
Brain-machine interface (BMI) can directly translate brain signals into commands to control an external device. BMI training for stroke enhances the volitional recruitment of surviving motor pathways and facilitates paretic muscle activity. Shindo et al. reported that after BMI training, finger extensor EMG activity appeared in 50% of patients (Shindo et al., 2011b). Therefore, we hypothesized that this training would be able to increase paretic finger muscle activity enough to apply HANDS therapy in patients with severe hemiparesis. BMI training might also increase the potential for application of HANDS therapy. Moreover, HANDS therapy following BMI training might improve UE motor function more than BMI training alone.
To confirm these hypotheses, we studied the effect of BMI training in patients with severe hemiparesis who could not extend their paretic fingers and who showed no EMG activity in the paretic finger extensors. We conducted tests to determine whether BMI training increases EMG activity in the paretic finger extensors enough to apply HANDS therapy. We also studied whether BMI training followed by HANDS therapy actually improved UE motor function more than BMI training alone.
Materials and methods
Participants
Participants were recruited from an outpatient rehabilitation clinic of a university hospital. Patients were included in the study if they met the following criteria: (i) a first unilateral subcortical stroke not involving the sensorimotor cortex, as confirmed by brain magnetic resonance imaging (MRI) or computed tomography (CT); (ii) time from stroke onset of more than 180 days; (iii) ability to raise the paretic hand to the height of the nipple; (iv) inability to extend the paretic fingers; (v) no motor improvement during the 30 days prior to starting the intervention, as confirmed by both the patients and their physicians; (vi) ability to walk independently in their daily lives; (vii) no severe cognitive deficits as determined by a Mini Mental State Examination score >25; (viii) no severe pain in the paretic UE; (ix) no pacemaker or other implanted stimulator; and (x) no history of seizures within the past 2 years and no use of anticonvulsants during the month before the intervention. We excluded the patients with visuospatial neglect according to tape bisection test. The patients with apraxia were also excluded with the assessment of gesture production.
From January 2012 to February 2013, 41 patients were seen in the outpatient clinic to be evaluated for this study. Twelve patients were excluded because they did not meet the inclusion criteria, and 29 patients were enrolled in the study. The study purpose and procedures were explained to the participants, and written informed consent was obtained from each. This study was approved by the Institutional Ethics Review Board and was registered at the University Hospital Medical Information Network (UMIN) Clinical Trial Registry (UMIN 000002121 and 000001986).
The study sample mean age was 50.6 years (SD 10.9), and the median time from stroke onset was 30.5 months (range, 9 to 180 months). Clinical details of the participants are shown in Table 1.
Brain-machine interface
Electroencephalography recording
Electroencephalography (EEG) was recorded with Ag-AgCl electrodes (1 cm in diameter), with a right ear reference at C3 in patients with right hemiparesis and at C4 in patients with left hemiparesis, according to the international 10–20 system. An additional electrode was placed at a position 2.5 cm anterior to C3 or C4. A ground electrode was placed on the forehead, and the reference electrode was placed on either A1 or A2 (ipsilateral to the affected hemisphere). EEGs were recorded in bipolar manner. The signals were digitized at 256 Hz using a biosignal amplifier (g.Mobilab+, g.tec medical engineering GmbH, Austria).
Event-related desynchronization (ERD) quantification
As a feature representing the participant’s motor imagery, the mu ERD, which is a diminution of the alpha band (8–13 Hz) of the mu rhythm amplitude, was used to control the BMI [9]. The ERD was expressed as the percentage of the power decrease related to the 1 s reference interval before the direction of imagery. The ERD at a certain frequency was calculated for each time and frequency according to the equation (1): ERD (f, t) = {(R(f) – A(f, t)) / R(f)}×100 (%); (1)
where A(f, t) is the power spectrum density of the EEG at a certain frequency band f [Hz] and time t [s] since the start of the imagery task, and R(f) is the power spectrum at the same frequency f [Hz] as that of the baseline period (Kasashima-Shindo et al., 2015).
BMI training
Motor imagery-based BMI training was carried out for approximately 45 min a day, 5 times a week, for a total of 10 days. All participants received 40 min of standard occupational therapy per day, which consisted of gentle stretching exercises, active muscle re-education exercises, and introduction to bimanual activities of daily living (ADLs). Details of the training protocol are described elsewhere (Shindo et al., 2011b); a brief overview is given here. The participants were seated in comfortable chairs, with their arms supported and relaxed on the armrest in pronation, and they faced a 39.1 cm computer monitor which was placed approximately 60 cm in front of them. A motor-driven orthosis with a servomotor was attached to the affected hand to achieve finger extension– flexion movement at the metacarpophalangeal joints.
A star-shaped cursor began to move at a fixed rate from left to right across the monitor over a 10 s period. The participants were instructed to rest for 6 s and then either to imagine extending their affected fingers or to remain relaxed for the next 4 s, depending on the task cue on the monitor. If the mu ERD was detected after the cue instruction to imagine finger extension, the cursor moved down on the screen as a visual feedback. Then the motor-driven orthosis extended their affected fingers for 5 s, and neuromuscular electrical stimulation was simultaneously applied to the paretic EDC muscle at the stimulus intensity of the motor threshold with surface electrodes. Each trial was performed at 30 s intervals. The training session consisted of 10 trials of motor imagery and 10 trials of relaxation, presented in a random order. Daily BMI training consisted of 3 training sessions. Before each training session, calibration was performed to adjust the EEG classification parameters, as described elsewhere (Guger et al., 2003). In a random order, the participants were asked either to imagine extension of their paretic fingers or to remain relaxed for 4 s. Each task was repeated 20 times.
Hybrid assistive neuromuscular dynamic stimulation (HANDS) therapy
The participants received closed-loop, EMG-controlled NMES (MURO solutions, Pacific Supply Co., Osaka, Japan) combined with a wrist-hand splint (Wrist Support, Pacific Supply Co.) for 8 hours a day over 3 weeks (HANDS therapy) (Fujiwara et al., 2009, 2015; Shindo et al., 2011a). The stimulus intensity and duration were controlled by EMG of the paretic EDC muscles (Muraoka, 2002). This NMES continually changes its stimulation intensity in direct proportion to the amplitude of the voluntary EMG. The surface electrodes pick up EMG signals at the target muscle and simultaneously stimulate it in direct proportion to the detected EMG signal, with the exception of the section of 25 ms after delivering each stimulation pulse, in which stimulation artifacts and M waves are observed. The details of the stimulator are described elsewhere (Fujiwara et al., 2009 Shindo et al., 2011a).
The rationale for combining the stimulation system with a wrist-hand splint was derived from the work of Fujiwara et al. (Fujiwara et al., 2004), who reported that a wrist-hand splint could reduce spasticity in the finger, wrist, and elbow flexors, and could facilitate finger extensor muscle activity. In our study, the HANDS system was active for 8 hours, and patients were instructed to use their paretic hand as much as possible while wearing it. Their non-paretic UE was not restrained. The patients were also instructed to practice bimanual ADLs.
The length of the intervention was 21 days, during which time all participants were admitted to hospital. They also received 90 minutes per day of occupational therapy, 5 days a week. Each session consisted of gentle stretching exercises of the paretic UE, active muscle re-education exercise, and instructions by occupational therapists on the use of their paretic hands in ADLs with the HANDS system. The therapists were directed to focus on the participants’ goals and their particular impairments and disabilities; thus, the specific therapy varied according to the needs of each patient.
Assessment
Assessment of paretic fine extensor muscle activity
The muscle activity of the paretic EDC, EPL, and flexor digitorum superficialis (FDS) was recorded with Ag-AgCl surface electrodes with diameters of 9 mm (Nihon Koden, Tokyo, Japan). The electrodes were applied with center-to-center spacing of 20 mm and were placed parallel to the muscle fibers and distal from the motor points of individual muscles. Before the electrodes were attached, the skin areas were rubbed with alcohol, and the skin resistance was kept below 5 kΩ. A Neuropack 8 EMG machine (Nihon Kohden, Tokyo, Japan) was used to record and analyze the EMG data. The bandpass filter was set at 30 Hz to 2 kHz. To ensure that the position of the EMG electrodes was identical at every recording session and to avoid variation of electrode placement, the exact position of the electrodes (contour) was re-drawn daily with a permanent marker. The patients were placed in a comfortable chair with their arms on an armrest, and the angle of their elbows was kept at 70–90 degrees. They were instructed to rest for 4 s and then to extend their affected fingers for the next 4 s. After trying to extend their affected fingers, they were instructed to rest for 4 s. The EMG data from 4.5 s to 7.5 s were designated as the finger extension task phase. We used the EMG data from 0 s to 3.5 s and from 8.5 s to 12 s for the rest phase.
We took into account the influence of the crosstalk from the FDS to the extensor muscle when interpreting the EMG amplitude of the EDC and the EPL. Mogk has reported that less than 2% of the common signal was present between the flexor and extensor electrode pairs during both the pinch and the grasp tasks (Mogk and Keir, 2003).
Patients underwent HANDS therapy if they had met the following criteria after BMI training: (i) The value of the maximum EMG amplitude evaluations for the EDC or EPL muscles minus 5% of the amplitude for the FDS at the same time during the extension task phase was over 100 μV; (ii) the average EMG amplitude evaluations for the EDC or EPL muscles in the rest phase were less than 20 μV.
Clinical assessment
UE motor function was assessed with the Fugl-Meyer Assessment UE motor score (FMA) (Fugl-Meyer et al., 1975). The FMA consists of four categories: A) shoulder/elbow/forearm; B) wrist; C) hand; D) coordination; maximum score: 66. It is a commonly used measure with excellent inter-rater reliability and construct validity (Platz et al., 2005).
The Motor Activity Log (MAL) is a structured interview used to measure UE disability in ADLs. The MAL-14 includes 14 items, scored on an 11-point amount of use (AOU) score (range 0–5) to rate how much the arm is used (Uswatte et al., 2005). High construct validity and reliability of the MAL have been demonstrated in patients with chronic stroke (Van der Lee et al., 2004; Uswatte et al., 2005). We calculated the sum of each items as the MAL-AOU. Spasticity of the fingers, wrist, and elbow was measured with the Modified Ashworth Scale (MAS) (Bohannon and Smith, 1987). These three clinical measures were scored by a blinded examiner, who did not know which patients were recruited for this study. This examiner assessed all the patients with stroke, who were admitted to our department during the study period, including patients not recruited for this study. These clinical assessments were performed before BMI training (pre-BMI), after BMI training (post-BMI), after HANDS therapy (post-HANDS), and 3 months after HANDS therapy (3m-HANDS).
Statistical analyses
After the normality of data distribution was examined with the Kolmogorov-Sminov test, repeated measure analysis of variance (ANOVA) was used in the analysis of the total FMA score (FMA-total), the score of FMA category A (FMA-A), the score of FMA category B (FMA-B), the score of FMA category C (FMA-C), the score of FMA category D (FMA-D), and the MAL-AOU with a main effect of Time (pre-BMI, post-BMI, post-HANDS, and 3m-HANDS). The paired t-test was used in the post hoc analysis. The MAS of the elbow, wrist, and fingers was examined with the Friedman test. The Wilcoxon signed-rank test was used in the post hoc analysis because the MAS data were not normalized.
In the MAS score, score 1+ was transformed to 2, and scores 2 and 3 were transformed to 3 and 4. The effects were considered significant if P < 0.05. All statistical analyses were performed with SPSS, version 23.
Results
Paretic fine extensor muscle activity
After BMI training, 21 of 29 patients fulfilled the criteria of EMG activity for HANDS therapy. Figure 1 shows the typical changes of EMG activity of the affected EDC from before to after 10 days of BMI training in one patient.
Overall time effects
Eighteen of 21 patients participated in the HANDS therapy (Fig. 2). Three of 21 subjects did not participate in this therapy because they could not afford to remain in hospital for a further 3 weeks. The mean interval from the end of BMI therapy to the beginning of HANDS therapy was 8.6±6.8 months. Repeated measure ANOVA showed a significant main effect of Time (pre-BMI, post-BMI, post-HANDS, and 3m-HANDS) in the FMA-total, the FMA-A, the FMA-B, the FMA-C, and the MAL-AOU in 18 patients (Table 2). The Friedman test showed a significant main effect of Time (pre-BMI, post-BMI, post-HANDS, and 3m-HANDS) in the MAS of the elbow, the wrist and the fingers (Table 2).
We did not find any negative change of face, trunk and leg function.
Post-hoc time effects
The effect of BMI training
The post hoc paired t-test showed significant improvement of the FMA-total, the FMA-A, the FMA-C, and the MAL-AOU between the pre-BMI and the post-BMI, but no significant change in the FMA-B (Table 2).
The post hoc Wilcoxon signed-rank test showed significant improvement in the MAS of the elbow and the fingers between the pre-BMI and the post-BMI, but no significant change in the MAS of the wrist (Table 2).
The effect of HANDS therapy after BMI training
The post hoc paired t-test showed significant improvement of the FMA-total, the FMA-A, the FMA-B, the FMA-C, and the MAL-AOU between the post-BMI and the post-HANDS (Table 2).
The post hoc Wilcoxon signed-rank test showed significant improvement in the MAS of the elbow and the fingers between the post-BMI and the post-HANDS (Table 2).
Three-month follow-up
The post hoc paired t-test showed significant improvement of the FMA-total, the FMA-A and the FMA-C between the post-HANDS and 3m- HANDS (Table 2).
The post hoc Wilcoxon signed-rank test showed significant improvement in the MAS of the wrist between the pre-BMI, the post-BMI and 3m-HANDS (Table 2).
Discussion
To our knowledge, this is one of the first study to demonstrate the efficacy of BMI training followed by HANDS therapy. This sequential rehabilitation program improved UE motor function in patients with severe hemiparesis, for whom there are few other effective therapies.
BMI has been shown to be an effective therapy for patients with severe hemiparesis who cannot move their paretic fingers (Shindo et al., 2011b; Ramos-Murguialday et al., 2013). HANDS therapy combined with BMI training improved the FMA score, with a mean gain of 9.2. This gain represents a clinically important difference for treatment-induced gains in the setting of chronic stroke (4.25 points on the FMA) (Page et al., 2012). In our study, BMI training alone improved the FMA with a mean gain of 3.3. A previous study showed a mean gain of the FMA with BMI training of 3.4 in patients with chronic severe hemiparesis (Ramos-Murguialday et al., 2013).
In a previous report, the mean gain of the FMA with HANDS therapy in patients with severe hemiparesis was 7.7 (Fujiwara et al., 2015), while our study showed the mean gain of HANDS therapy to be 5.9. The difference in the gain may be explained by the difference in the score before HANDS therapy. The mean FMA score before HANDS therapy in our study was 23.1, but it was 33.3 in a previous study (Fujiwara et al., 2015).
We found further improvement in the MAL-AOU with BMI followed by HANDS therapy than with BMI training alone. HANDS therapy may induce dose-dependent functional recovery and task-specific improvement because patients use their paretic hand in their ADLs. These results confirmed our hypothesis that BMI followed by HANDS therapy resulted in more functional recovery than with BMI training alone.
Shindo et al. reported that new voluntary finger extensor EMG activity developed in 4 of 8 patients (50%), although they had shown little or no finger extensor EMG activity before BMI training (Shindo et al., 2011b). In our study, 21 of 29 participants showed new voluntary finger extensor EMG activity, which fulfilled the criteria for HANDS therapy. The success rate for transfer from BMI to HANDS therapy was 72.4%, which we believe justifies the clinical use of BMI to induce paretic finger extensor activity.
Mechanism for BMI to increase paretic muscle activity
Our BMI system was triggered with ERD at the affected motor cortex during motor imagery, which is a reflection of motor cortex activity. Takemi et al. showed that the magnitude of ERD during motor imagery represents the motor cortex excitability, which was measured as the motor evoked potential (MEP) and the downregulation of intracortical inhibitory interneurons (Takemi et al., 2013). BMI training, repetitive motor imagery, and sensory motor stimulation with passive movement and electrical stimulation all increased motor cortex excitability in the affected hemisphere (Shindo et al., 2011b). It is hypothesized that increased motor cortex excitability may increase the descending volley to the target muscle. It is also possible that the neural link between brain activity and paretic limb movements influences the specific neural network activity of the visuomotor loop involved in a motor task. This neural link may strengthen the associative connection between a movement attempt and an actual finger movement, which is an example of Hebbian plasticity (Jackson et al., 2012). Increased corticospinal excitability and strengthening of the specific neural network involved in finger extension can induce actual finger extensor muscle activity (Ramos-Murguialday et al., 2013).
BMI improved FMA-A and C but not B and D. Our BMI system trained to extend the paretic fingers. Therefore we found task specific finger function improvement after BMI. It is supposed that BMI training increased the awareness of paretic arm and use of the paretic UE in their ADL. That may explain the improvement of proximal arm function. BMI reduced muscle spasticity in elbow. Reducing spasticity in elbow may reduce the synergy pattern and improve the FMA-A score. The items of FMA-D are difficult task for severe hemiparetic patients. Mean FMA-D value before FMA-D was 0.1. That means most of participants in this study could not touch their nose with their paretic hand. It is difficult to change the FMA-D items in severe hemiparetic patients. Patients, who cannot extend their paretic fingers, extend the finger using tenodesis-like action. When they want to extend their paretic fingers they flex their wrist. In their ADL, they use this tenodesis-like action. It may explain one of the reason why BMI did not improve the elbow spasticity andFMA-C.
Mechanism for HANDS therapy to improve UE motor function
HANDS therapy following BMI training further improved UE motor function and increased use of the paretic hand. A previous study has reported that electrical stimulation combined with voluntary contraction of the target muscle with closed-loop, EMG-triggered NMES, induced downregulation of intracortical inhibitory interneurons, with subsequent facilitation of corticospinal activity in the intended movement (Fujiwara et al., 2015). HANDS therapy provides day-to-day assistance whenever patients attempt to extend their paretic fingers. Co-activation of the brain and the spinal cord may strengthen the surviving connections between the two sites due to Hebbian mechanisms (Jackson et al., 2012).
With HANDS therapy, the patients learned how to use their paretic UE in their ADLs. Therefore, daily use of the paretic hand after HANDS therapy may result in use-dependent recovery, which might explain the further improvement of the MAL-AOU after this therapy.
In general, the process of stroke rehabilitation should be state-dependent and goal-oriented. Treatments might target several different problems, from relieving very specific impairments, to improving activity and participation (Langhorne et al., 2011).
Actual participation by the patients in use of their paretic UE after BMI training was limited. The mean sum of the MAL-AOU score of 5.3 signified that patients did not use their paretic UE for most of the MAL-AOU items. Consequently, we believe that the goal of BMI should be facilitation of paretic finger muscle activity, and that the goal of HANDS therapy should be improved participation of patients in use of their paretic UE in their daily lives. We were able to improve use of the paretic UE with HANDS therapy. The mean sum of MAL-AOU became 11.1 after HANDS therapy, which means that patients used their paretic UE in most items of the MAL-AOU.
There are, however, several limitations to this study. The number of patients treated in this study was small and follow up data was limited in post HANDS therapy. Participants of this study are limited in patients with subcortical lesion and 24 out of 29 participants are hemorrhagic stroke patients. We should consider the influence of the type of stroke on the effect of BMI since ischemic stroke patients frequently have cortical lesions. There was no age-matched control or sham treatment group. Despite these limitations, however, we believe that the present findings provide important information for the treatment of chronic stroke patients with severe UE hemiparesis. The pilot data presented in this study provide the basis for designing and conducting a larger-scale trial with a more rigorous study design, including masking and randomization, to test the hypothesis that this training program is more effective and less labor intensive than other strategies in the management of the chronically paretic UE.
Conclusions
In conclusion, functional recovery from stroke has been induced with BMI training followed by HANDS therapy, even in patients with chronic and moderate-to-severe hemiparesis. This new therapeutic strategy may open a new door in stroke neurorehabilitation.
Footnotes
Acknowledgments
Funding sources: This study was partially supported by a Health Labor Sciences Research Grant (12102976); a JSPS KAKENHI (C) Grant (26350587); and by the Japan Agency for Medical Research and Development (AMED) and the Strategic Research Programs for Brain Sciences.
The authors thank Sawako Ohtaki for her contributions to this study.
Statements of authorship: MK and TF contributed to the conception and study design; data acquisition, analysis, and interpretation; and drafting of the manuscript. JU, KM, YM, and ML contributed to the conception and study design. AN, KH, KA, AN, and KM contributed to data acquisition. All authors revised the article critically and approved the final version for publication.