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ORIGINAL
Clinical Uses of a Robot (Hybrid-Assisted Limb or HAL™)
in Patients with Post-stroke Spasticity after Botulinum
Toxin Injections
Tsuyoshi Okuno1, 2, Toshiaki Takeuchi2, 3, Eiji Takeda1, Yuisin Izumi2, and Ryuji Kaji2, 3
Kenshokai Gakuen College for Health and Welfare, Tokushima, Japan, 2Department of Neurology, Tokushima University, Tokushima, Japan,
Department of Neurology, Utano National Hospital, Kyoto, Japan

1
3

Abstract : Spasticity is the major cause of disabilities in stroke-survivors. Botulinum neurotoxin (BoNT) injections have been used to reduce the muscle tone in those patients, but its efficacy in functional outcome is notwell delineated. We have studied the effect of a robot (Hybrid-Assisted Limb or HAL™) designed for assisting theelbow flexion and extension in those who underwent BoNT injections with reduced muscle tone. We enrolled
15 post stroke patients who had BoNT injections for more than 12 months. They were measured for active ROM(range of motion) with video recordings before and after the use of HAL for 40 minutes. Active ROM was measured by a rater who were blinded as to the use of the robot. Significant increase of active ROM was observed immediately after the use of HAL, and the effect was maintained for another 12 months by repeating the sessions. Itis suggested from present study that the combined use of BoNT and robotics is effective efficacious for regaining
the active function of the upper limb in stroke survivors. J. Med. Invest. 68 : 297-301, August, 2021
Keywords : Stroke, spasticity, botulinum, robotics, hybrid-assisted limb

INTRODUCTION
Paralysis of the upper limbs is seen in up to 85% of stroke
survivors (1), and 25% of them develop total loss of the functionof the limb by 5 years after the stroke onset (2). Among thosesurvivors, it has been estimated that 38% of them suffer fromspasticity (3). According to the estimation of Japanese government in 2017, the number of those stroke survivors in Japanamount to 1.2 million, and those with total loss of the upper limb
function are 0.3 million. Thus those disabilities cause the lossof independence in activities of daily life, lack of self-esteem of
those survivors and the increased burden of care in the society.
It would be desirable to find a method for those with upper limb
disability to regain its active function in order to reduce not only
the cost of care in Japan but also the global burden of disease (4).
Botulinum neurotoxins (BoNTs) have been approved for spasticity treatment in many countries. There is strong evidence thatthey reduce muscle tone in spasticity (5, 6), but it is uncertain
whether they are useful in improving functional disabilitiesof the limbs such as increasing active range of motion (ROM).
Spasticity is defined as increased muscle tone as a consequenceof upper motor neuron dysfunction or loss. Since it develops laterin the course of acute stroke that damages the upper motor neuron, there seems to be a maladaptive synaptic plasticity at multiple levels including the spinal cord (7). BoNTs have been shownto have direct central action after its injection into the muscle (8),and it could regain active function of the limb if combined withmeasures that influences the synaptic plasticity.
Robotic have been used for neurorehabilitation, and Hybrid-Assisted Limb (HAL®, Cyberdyne Co Ltd., Japan) is now
being approved for spinal cord injury in many countries. The
Received for publication May 10, 2021 ; accepted May 25, 2021.
Address correspondence and reprint requests to Tsuyoshi Okuno,
Kenshokai Gakuen College for Health and Welfare, 369-1 Higashi
takawa, Tenma, Kokufu-cho, Tokuhsima, 779-3105, Japan andFax : +81-88-642-9227.

latter is designed to pick up electrical signals in the muscle tocontract, and to mechanically assist the joint to move as desired
without time delay. It utilizes the principle of paired associative
stimulation (PAS) (9), which links the desire to move and theactual movement evoked proprioceptive feed-backs, resulting inplastic changes (10).
We planned the object of this study into investigate whether
the combination of BoNT injection and robot rehabilitation using
HAL could increase active ROM compared to the ehhect of single
BoNT injections (11).

SUBJECTS
We screened 35 patients with post-stroke spasticity who had
been treated with BoNT injections for more than 12 months (or3-4 sessions of 200-300 units of onabotulinumtoxinA). After excluding those who could not accept the purpose of the study andwere not adaptable to the robot (n = 10), we enrolled 25 patientsfor the study period, after obtaining informed consent. Those
who were unable to visit regularly for the robot therapy or BoNT
injections (n = 10) were also eliminated. Total of 15 patients wereanalyzed (Fig. 1). Baseline characteristics of the patients areshown in Table 1.
This study was approved by the Institutional Review Board(No.2483) of the Tokushima University (Tokushima, Japan).
The procedures were fully explained to subjects and an informed
consent form was signed.

METHODS
The robot was a machine fitted for the elbow joint, or single-joint HAL (HAL-SJ ; Fig. 2), which detects muscle activitiesof the elbow flexor (biceps brachii muscle) and the extensor(triceps brachii muscle). The electric signals triggered the robot
arm, which instantly (< 50msec) flexes or extends the elbow.
The patients were evaluated for active ROM by videotaping

The Journal of Medical Investigation Vol. 68 2021

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298

Table 1. Baseline characteristics of the patientsInterval from Brunnstorom
onset (year)
stageCaceAge(year)

GenderHandedness

Diagnosis

Location of lesion

153

Male

RightIschemia

Internal carotid artery (ICA) dissection

6ⅢⅡ

269

Male

Right

Ischemia

Middle carebral artery (MCA) occulusion

9348

FemaleRight

Hemorrhage

putamen

8Ⅱ

469

Male

Left

Hemorrhage

putamen8Ⅱ

570

FemaleRight

Hemorrhage

putamen

19Ⅱ

660

Male

Right

Hemorrhage

putamen

11Ⅳ

765

Male

Right

Hemorrhage

putamen

12Ⅳ

873

Male

Left

Ischemia

Corona radiata

5Ⅳ

968

Male

RightIschemia

Middle carebral artery (MCA) occulusion

7Ⅳ

1073

MaleLeft

Ischemia

Corona radiata

8Ⅳ

1175

Male

LeftIschemia

Corona radiata

6Ⅳ

1273

Male

Right

Hemorrhage

putamen8Ⅳ

1368

FemaleLeft

Hemorrhage

putamen

10Ⅲ

1459

Male

Right

Ischemia

Cardioembolic

6Ⅱ

1564

FemaleRight

Ischemia

Middle carebral artery (MCA) occulusion

7Ⅲ

Mean (SD)65.8 (7.8)

8.6 (3.4)

At 0 month, HAL was tried immediately after BoNT injection,
when BoNT effects were not apparent (HAL-SJ). At 1 monthafter the initial HAL training, when the BoNT effects were supposed to be maximum, HAL training session was repeated asHAL+BTX, which indicates the combined effects of BoNT andHAL for a single session. At 6 months, HAL was repeated withassessment (6mo), which mirrors the effect of 2 times of BoNT
injections and 4 HAL sessions. At 12 months after the start(1yr), assessment was made immediately after HAL training,reflecting 4 times of BoNT sessions and 6 times of HAL trainings. The subjects received the occasional rehabilitation (usually40 minutes / week) during the entire test period, and its protocol
was not changed.
All statistical analyses were performed using EZR (12). EZR
is a modified version of R commander designed to add statisticalFig 1. Flow diagram of patient selection.
after having BoNT injection (onoabotulinumtoxinA or BOTOX®
200-300units) into muscles at the shoulder, elbow and wrist
joints. Then they were fitted for HAL-SJ, and had a series oftest runs for 10-15 minues to confirm that the machine flexes
or extends the elbow at the patient’s will. After these tests, they
had 40 minutes session of the elbow joint movement training assisted by HAL-SJ. Before and immediately after these sessions,the patients were assessed for active ROM of the elbow joint byvideotaping. Additional evaluation was made as to modified Ashworth Scale (MAS) of the elbow joint, and Fugl-Meyer Assessment (FMA ; Upper Extremity-A items ; range 0-36). The sameprocedure was repeated at each of the following 4 sessions of 3
months interval (12 months), and all active ROM of the elbow
joint were taped for post hoc review by a rater blinded as to thetiming of HAL intervention.
The assessment schedule is depicted in Fig. 3. The changes ofactive ROM between 12 months before and immediately before
starting HAL rehabilitation (0 month) were assessed as Baseline, reflecting only the effects of BoNT injections without HAL.

Fig 2. The single-joint Hybrid Assistive Limb(HAL-SJ). The
controller showing the Bioelectrical signals.

The Journal of Medical Investigation Vol. 68 August 2021
functions frequently used in biostatistics. In addition, changes in
ROM were assessed with Bonferroni correction, MAS and FMA
were assessed with paired t-test and Wilcoxon’s signed-rank
test. For all outcome variable, the critical value for rejection of
the hypothesis set at P < 0.05. The effect size (d) was establishedby calculating the difference between the means of the experimental and control groups divided by the average population
standard deviation. The effect size was based on the classification of Cohen, it is classified as small (d ≧ 0.2), medium (d ≧ 0.5),and large (d ≧ 0.8).

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RESULTSThe changes of active ROM in each patient is depicted in Fig.4.
The effect of HAL was apparent immediately after the session(HAL-SJ ; p < 0.05, Bonferroni correction), but the effect size (d)was small (Table 2). After completing the combined BoNT andHAL interventions for a year (1-Year), active ROM increased
from 49.0 ± 33.7° to 63.3 ± 37.1°, which was significant after
multi-variance analysis (p < 0.05), and the effect size was medium. The other functional outcome, FMA-UE improved from
12.1 ± 3.9 to 14.6 ± 5.4, a significant increase (Table 3, p < 0.01,

Fig 3. Summary of the patient’s clinical course.

Fig 4. Active range of joint motion change of elbow for 2 years.

T. Okuno, et al. Effects of BTX and Robot (HAL)

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Table 2. Active range of motion change of elbow and comparison with baselinenElbow jt-12month

Baseline

HAL-SJ

1month

6month12month15

ROM (°)

38.0 (28.8)

49.0 (33.7)

57.7 (37.6)

52.7 (34.6)

58.0 (36.7)

63.3 (37.1)

case (n = 15)

Outcomes

Baseline-12month

HAL-SJ

12monthActive ROM

P = 0.0217*

P = 0.0194*

P = 0.0146*

Effect size

0.382

0.257

0.425

*Bonferroni correction (Multi-variance analysis)
Effect size(d) = 0.20(small), 0.50(medium), 0.80(large)

Table 3. Changes in functional outcomes
Outcomes

Baseline
Mean (SD)

Baseline+1year
Mean (SD)P value

Fugl-Meyer Assessment

Proximal

12.1 (3.9)

14.6 (5.4)

P=0.001*

Modified Ashworth Scale

Elbow-flexor

1.6 (0.3)

1.4 (0.4)

P=0.047***Wilcoxon rank-sum test **Paired t-testpaired-t test). It is however noted that the changes of active
ROM was also significant during the period of 1 year before
the start of HAL using only BoNT injections (38.0 ± 28.8° to49.0 ± 33.7°). MAS slightly improved from 1.6 ± 0.3 to 1.4 ± 0.4(Table 3, p < 0.05, Wilcoxon rank-sum test).

DISCUSSION
The present study clearly demonstrated immediate beneficial
effects on active ROM of robot rehabilitation using HAL in thosepatients who had undergone BoNT injections previously. If thejoint was rigid by severe spasticity, it would not have been possible to use HAL because of its mechanical limitations to safety. It
is therefore clear that the combination of BoNT and HAL could
increase the active function of the limb. It’s long term effects
were also supported at 1 year considering the effect size, but it is
not clear whether the combination therapy was superior to BoNT
injections with conventional rehabilitation alone.
The mechanism of spasticity has been explored in the past,
but its precise mechanism is not fully understood. Spasticity
is a syndrome of increased muscle tone caused by upper motor
neuron dysfunction with exaggerated deep tendon reflexes (13,14), but the acute loss of upper motor neuron does not cause
spasticity. Spasticity develops after sometime in the course of
stroke convalescent period. Therefore it appears that maladaptive synaptic plasticity at least in the spinal cord may be the key
factor for its development. BoNT injections influences central
synapses directly or indirectly (8), and may rectify the abnormal
neuroplasticity at the spinal cord level.
Paired-associative stimulation (PAS) is a well-establishedphysiological phenomenon (15). It refers to a paradigm consistingof repetitive median nerve stimulation combined with transcranial magnetic stimulation (TMS) over the contralateral motor
cortex. This protocol has been shown to induce plastic changes of
excitability in the brain, and its presumed mechanisms include
long-term potentiation (LTP), a cellular mechanism likely to berelevant for learning and memory. Of particular importance isthe fact that PAS-induced changes of the size of amplitudes ofthe motor evoked potentials (MEPs) depends on the exact interval between the afferent and the magnetic pulse during theintervention.
The mechanism of the immediate effect of HAL in the present
study seems to be similar to PAS : the intention to move thejoint, a self-initiated cortical stimulation, is combined without
time delay with the actual movement perceived through theproprioceptive input back to the cortex, possibly resulting in LTP
at the cortical level. Since the stroke patients do not have normal
upper motor neurons at the primary motor cortex, the magneticstimulation over the diseased cortices is not feasible. The limb
movement-induced inputs to the remaining cortices by utilizing
HAL would be more practical than the transcranial magneticstimulation (10, 11).
In conclusion, the present study demonstrated immediate effects of improving active ROM of the elbow joint in patients withdecreased spasticity due to stroke who had had BoNT injection
for more than 1 year. Its long-term effects were promising infurther ameliorating the active function of the limb.

CONFLICT OF INTEREST
The authors have no conflict of interest declare.

ACKNOWLEDGEMENTS
The authours thank the study participants and members of
our laboratory, the staff of Kenshokai Gakuen.

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