Effect of cyborg-type robot Hybrid Assistive Limb on patients

with severe walking disability in acute stroke: A randomized

controlled study

Chiaki Yokota, M.D., Ph.D,a Kenta Tanaka,b Katsuhiro Omae, Ph.D.,b

Masatoshi Kamada, PT,a Hiroyasu Nishikawa, PT,a Masatoshi Koga, M.D., Ph.D,c
Masafumi Ihara, M.D., Ph.D,d Yasuyuki Fujimoto, PT,a Yoshiyuki Sankai, Ph.D.,e
Takashi Nakajima, M.D., Ph.D.,f and Manabu Minami, M.D., Ph.Db

Objectives: To investigate whether early gait training using Hybrid Assistive Limb
(HAL) is feasible and improves walking and independency compared with conven-
tional physical therapy (CPT) in patients with severe walking disability after stroke.
Methods: We conducted a single-center, randomized controlled study. Patients with
first-ever stroke who had severe walking disability were included. All patients
started gait training within 10 days post-stroke onset. Twenty-four patients were
randomly assigned into HAL or CPT groups. Outcome measures were collected at
three time points, at baseline, completion of 20 sessions of gait training (second
assessment), and 3 months after the initiation of gait training. The primary out-
comes were changes in motor sub-scores of the Functional Independence Measure
or Functional Ambulation Category at the completion of the second assessment
from baseline. Results: Twenty-two patients (median age, 68 years; 12 patients in
the HAL group and 10 patients in the CPT group) completed the study. There were
no significant differences in primary outcomes. Apathy scale, one of the secondary
outcomes, showed a decreasing trend in the HAL group (mean change of -3.8, 95%
CI -8.14 to 0.475), and a slight increasing trend in the CPT group (mean change of
1.2, 95% CI -2.66 to 5.06) at the second assessment. Patients in the HAL group expe-
rienced no adverse events. Conclusions: Early gait training in patients with severe
walking disability after stroke using HAL was feasible. Walking ability and inde-
pendency were not improved at the completion of 20 sessions of gait training.
Keywords: Robot-assisted rehabilitation—Gait training—HAL—Apathy scale
© 2023 The Author(s). Published by Elsevier Inc. This is an open access article under
the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

From the aDepartment of Stroke Rehabilitation, National Cerebral and Cardiovascular Center, 6-1 Kishibe-Shimmachi, Suita, Osaka 564-8565,
Japan; bDepartment of Data Science, National Cerebral and Cardiovascular Center, 6-1 Kishibe-Shimmachi, Suita, Osaka 564-8565, Japan; cDepart-
ment of Cerebrovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Japan, 6-1 Kishibe-Shimmachi, Suita, Osaka 564-8565,
Japan; dDepartment of Neurology, National Cerebral and Cardiovascular Center, 6-1 Kishibe-Shimmachi, Suita, Osaka 564-8565, Japan; eCenter for
Cybernics Research, University of Tsukuba, Tsukuba 305-8573, Japan, CYBERDYNE Inc; and fNiigata National Hospital, National Hospital Orga-
nization, 3-52 Akasaka, Kashiwazaki City 945-8585, Japan.
Received October 13, 2022; revision received December 20, 2022; accepted January 19, 2023.
Corresponding author. E-mail: cyokota@ncvc.go.jp.
1052-3057/$ - see front matter
© 2023 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/)
https://doi.org/10.1016/j.jstrokecerebrovasdis.2023.107020

Journal of Stroke and Cerebrovascular Diseases, Vol. 32, No. 4 (April), 2023: 107020 1
2 C. YOKOTA ET AL.
Introduction
Post-stroke rehabilitation is essential to improve quality
of life, return independency to premorbid conditions, and
reduce national healthcare budgets. Remarkable techno-
logical innovations in recent years have allowed advanc-
ing of robot-assisted rehabilitation after stroke.
Electromechanical-assisted gait training combined with
physical therapy was reported to increase the chance of
regaining independent walking ability after stroke. 1 With
treatment, enhanced plasticity, which was associated with
a time-dependent expression of both neuronal growth-
promoting and -inhibiting genes, and neuroanatomic
changes, including synaptogenesis in the peri-infarct and
remote tissues, occurred within the first week.2 4 Thus,
task-specific motor training with robot-assisted rehabilita-
tion initiated earlier after stroke is expected to facilitate
functional recovery. However, there is little evidence of
the efficacy of earlier initiation of gait training within a
few weeks after stroke onset with robot-assisted rehabili-
tation.1 Further, it is also important to identify the specific
population of patients with stroke who are suitable for
early robot-assisted rehabilitation.
In patients 2 6 weeks post-stroke, Morone et al.5
reported that only patients with more severe impairment
in motor leg function benefited from robotic therapy in
combination with conventional therapy. Nilsson et al. 6
showed that the exoskeleton Hybrid Assistive Limb
(HAL; Cyberdyne Inc., Tsukuba, Japan) enabled intensive
training of gait in hemiparetic patients with severe
impaired gait function early after stroke. We also previ-
ously demonstrated through an observational study that
patients initiating rehabilitation with a higher dose-inten-
sive gait training combined with HAL within the first
week post-stroke improved the independent walking abil-
ity, compared with patients rehabilitated using physical
therapy without HAL. This was particularly evident in
patients with severe lower limb motor impairments. 7
Robot-assisted rehabilitation could allow patients with
greater motor impairment to increase the dosage and
intensity of therapy. Therefore, we hypothesized that gait
training with HAL targeted at patients with severe walk-
ing disability should amplify or accelerate reconstruction
of neural network to regain walking ability in acute stroke
rehabilitation.
Conversely, motivating patients to wrestle with goal-
directed training for functional recovery is difficult in
acute stroke rehabilitation, especially in patients with
severe disability. About one third of patients have acute
stroke have apathy, 8 which is defined as reduced motiva-
tion that cannot be attributed to loss of consciousness,
cognitive impairment, or emotional distress.9,10 Post-
stroke apathy has a negative impact on recovery after
stroke.11 13 We reported that apathy at discharge was a
significant determinant of decreased physical activity at 3
months after onset even in patients with minor stroke or
transient ischemic attack. 14 Thus, in addition to func-
tional recovery, neuropsychiatric symptoms, such as apa-
thy, should also be assessed as an outcome measure in
clinical studies of stroke rehabilitation.
Here we report a randomized controlled study investi-
gating whether early gait training using HAL is feasible
and improves better walking ability compared with con-
ventional physical therapy without using HAL, which
was initiated within 10 days of acute stroke onset in
patients with severe walking disability. In the present
study, we examined the effect of the gait training using
HAL on the apathy as the secondary outcome in addition
to examine the walking independency and ability as the
primary outcome.
Methods
Design
We conducted a single-center, parallel-group, random-
ized controlled study. This study was approved by the
Institutional Research and Ethics Committee (M30-119-4)
and registered with the UMIN clinical trial (ID:
UMIN000034802). Written informed consent was
obtained from all participants. The present study was con-
ducted in accordance with the Declaration of Helsinki and
Ethical Guidelines for Medical and Biological Research
Involving Human Subjects in Japan.
Participants
Patients with acute stroke admitted to the National
Cerebral and Cardiovascular Center within 48 h of stroke
onset from November 2018 to March 2021 were recruited
to the present study. Inclusion criteria were as follows: (1)
aged 20 and <85 years old; (2) first-ever stroke; (3) mod-
erate to severe walking disability defined as a score of
20 on the lower extremity sub-score in the Fugl-Meyer
Assessment15,16 at baseline as reported previously,7 (4)
ability to start gait training within 10 days of stroke onset.
Major exclusion criteria were as follows: (1) communica-
tion difficulties due to impaired consciousness, aphasia,
and/or cognitive dysfunction; (2) difficulty in performing
gait training exercises due to orthopedic disease; (3) dialy-
sis patients; (4) difficulty in fitting in the robot-suit HAL;
(5) patients with deep venous thrombosis who are high
risk for embolic events; (6) patients with mental disorders
or cognitive impairment who are unable to use HAL
safety; (7) patients with severe involuntary movements of
lower extremities; (8) patients with dermatological condi-
tions who are difficulty in putting the electrodes on the
skin; (9) patients with gait impairment due to cerebral or
muscle disorders other than acute stroke; (10) pregnant
women; and (11) patients who are participating or intend
to participate other clinical trials during the study period
of the present study.
EFFECT OF CYBORG-TYPE ROBOT HYBRID ASSISTIVE LIMB
Sample size calculation
Assuming a standard deviation of 11 for one of the pri-
mary outcomes (changes of Functional Independence
Measure [FIM] motor sub-score) from the results of the
previous study,7 the half range of 95% confidence interval
(95% CI) of the difference between two treatment groups
was calculated to be 9.784 when we enrolled 11 patients
per group. We thought this accuracy was enough to detect
a clinically significant difference. Assuming a dropout
rate of 10%, the aim was to recruit 12 patients in each
group (24 subjects in total).
Randomization and allocation
After the baseline assessment, patients were randomly
assigned in a 1:1 ratio to undergo either robot-assisted
gait training using HAL combined with conventional
physical therapy (HAL group) or gait training with con-
ventional physical therapy alone (CPT group). We used
an internet-based dynamic randomization system to bal-
ance the two groups with respect to age (<75 years vs.
75 years or older), sex, and stroke subtype (ischemic vs.
hemorrhagic).
Device
A biped non-medical model of HAL-FL05 was chosen
in the present clinical setting according to Japanese device
regulation. HAL is an exoskeleton, cyborg-type robot
based on the fusion of humans, robots, and information
systems. 17 According to Japanese device regulation, a
non-medical model of HAL lower limbs type, HAL-FL05,
comparable to the medical model HAL-ML05, was chosen
in the current clinical setting. There was no difference,
except that there is no filter for minute bioelectrical signals
in the non-medical model and that it only follows the Jap-
anese welfare equipment regulations.
Gait training program
The gait training was initiated within 10 days after the
onset of the index stroke. A total of 20 sessions (20 min
per session) of the gait training was completed in all
patients. The gait training program was consisted of 1 3
sessions per day (20 min per session), and 5 or 6 days a
week, with a total of 20 sessions. In the HAL group, gait
training with HAL was combined with physical therapy,
which was 3 days a week with HAL and another 2 or
3 days a week with conventional physical therapy. A typi-
cal training session lasted 40 minutes, including time for
intermittent resting time according to patients’ conditions.
During HAL training, a mobile hoist (ROPOX ALL IN
ONETM) was used to prevent falls and adjust the patient’s
posture, and patients underwent gait training overseen
by two physical therapists as described previously.7 In
the CPT group, the training program includes standing,
weight shifting, stepping, over-ground walking with
3
manual assistance by the physical therapist as conven-
tional manners. After both groups completed training, all
patients were discharged to a rehabilitation hospital to
continue gait training until 3 5 months after the onset of
the index stroke. In these hospitals, the patients under-
went conventional physical therapy alone, for at least 3
sessions per day (20 min per session) but did not receive
gait training with HAL.
Outcome measures
We registered baseline data, including demographic
data, risk factors, stroke subtype, with or without throm-
bolytic therapy, and stroke severity assessed using the
National Institute of Health Stroke Scale (NIHSS) score.18
Outcome measures were independence in activities of
daily living assessed by FIM including the FIM total score,
motor sub-score, and cognitive sub-score,19 walking abil-
ity assessed by Functional Ambulation Category (FAC), 20
motor impairment assessed by FMA, motor sub-score,
lower extremity sub-score, balance sub-score,15,16 inde-
pendence of daily life assessed by modified Rankin Scale
score,21 and the apathy scale (with a score ranging from 0
to 42; higher scores indicate more severe apathy).22
Outcome measures were collected at three time points
during the study period, i.e., at registration (baseline
assessment before randomization), completion of 20 ses-
sions of gait training (second assessment), and 3 months
after the initiation of gait training (third assessment). At
the third assessment, patients were asked to visit our hos-
pital to follow up examinations. FIM was also assessed at
the completion of 10 sessions of the gait training (mid-
point, MP) in both groups in addition to the three time
points for catching the rapid walking independence in the
early phase. All assessments in the HAL group were per-
formed when the participants were not wearing the HAL.
Assessments of each time point were examined by physi-
cal therapists other than those in patient’s charge.
The primary outcomes were as follows: (1) changes of
FIM motor sub-score (DFIM motor sub-score) at the sec-
ond assessment from baseline; (2) changes of FAC
(DFAC) at the second assessment from baseline. Second-
ary outcomes were changes of the other outcome meas-
ures at each time point from baseline including FIM total,
FIM motor sub-score, FIM cognitive sub-sore, FAC, FMA
total, FMA motor sub-score, FMA lower extremity sub-
score, FMA balance sub-score, mRS, and apathy scale.
Further, we collected data of adverse events including
skin troubles associated with wearing HAL, myalgia or
arthralgia associated with the gait training, falls, symptom
deterioration with NIHSS score 2, stroke recurrence, and
the occurrence of cardiovascular events and infectious dis-
eases until the third assessment. Adverse events were
assessed through the medical charts in our hospital or by
querying those from the rehabilitation hospital.
4 C. YOKOTA ET AL.

Fig. 1. Flowchart for study participants.

CPT, conventional physical therapy; HAL, Hybrid Assistive Limb.

Statistical analyses Table 1. Baseline characteristics.

The full analysis set (FAS) was defined as patients HAL group CPT group
who received the study intervention and were assessed (n=12) (n=10)
for at least one outcome measure at baseline and at least
Age, years 65.3 (10.1) 62.5 (10.6)
one time point except for the baseline. We performed
Female 5 5
efficacy analysis in the FAS according to intention to Body mass index, kg/m2 23.2 (3.9) 23.8 (3.3)
treat. Data are reported as means with standard devia- Hypertension 10 10
tions or 95% CI. All reported P values are two-sided. Dyslipidemia 6 6
The primary outcomes were analyzed using a mixed- Diabetes mellitus 2 1
effect model for repeated measures (MMRM). We Atrial fibrillation 0 1
included the fixed categorical effects of group, time Ischemic/ Hemorrhagic 5/7 5/5
point, and group-by-time point interaction, as well as stroke
the fixed continuous effect of value at baseline. An NIHSS score 8.6 (4.3) 7.3 (3.3)
unstructured covariance structure was used to model Thrombolytic therapy 1 1
the within-patient errors, and Kenward-Roger approxi- For age, body mass index, and NIHSS score, values are mean
mation was used to estimate degrees of freedom. All values and values in parentheses are standard deviation. Other val-
ues are numbers.
MMRM analyses successfully converged and signifi-
CPT, conventional physical therapy; HAL, Hybrid Assistive
cance tests between two groups were performed based Limb; NIHSS, National Institute of Health Stroke Scale.
on least-squares means. All statistical analyses were
implemented with SAS version 9.4.
characteristics between the two groups. Table 2 shows
Results
outcome measures at baseline. Mean FAC in the CPT
A total of 1,875 patients (female 743; mean age of 74.2 group was somewhat lower than in the HAL group, but
years) were screened for eligibility during the recruitment other values were generally similar in both groups.
period. Twenty-four patients (12 patients in the HAL There were no significant differences in the primary
group and 12 patients in the CPT group) were enrolled in outcome measures, i.e., DFIM motor sub-score and
the present study. Two patients in the CPT group with- DFAC at the 2nd assessment, between the two groups
drew from the study; one patient rejected by oneself to (Table 3A, Fig. 2A, B). In the secondary outcomes, at the
participate after randomization, and one patient with second assessment, the HAL group showed a decreas-
putaminal hemorrhage underwent the ventricular drain- ing trend in the apathy scale (mean change of -3.8, 95%
age due to hydrocephalus 4 days after starting the rehabil- CI -8.14 to 0.475), while the CPT group showed a slight
itation. Efficacy analysis was performed for 22 patients (12 increasing trend (mean change of 1.2, 95% CI -2.66 to
from the HAL group and 10 from the CTP group) who 5.06). However, this difference in trend was less pro-
were included in the FAS (Fig. 1). There were no missing nounced at the third assessment. Other secondary out-
data in the FAS. comes at each time point were not remarkably different
Baseline characteristics are summarized in Table 1. between the two groups (Table 3B, Table S1A & S1B in
There were no significant differences in patient the Supplementary Appendix).
EFFECT OF CYBORG-TYPE ROBOT HYBRID ASSISTIVE LIMB 5

Table 2. Outcome measures at baseline. assessment. One patient in the CPT group underwent the
ventricular drainage due to hydrocephalus. Patients in
HAL group CPT group the HAL group experienced no adverse events.
(n=12) (n=10)
Motor and functional recovery after stroke onset is the
FIM total score 69.3 (12.8) 70.1 (12.0) most dramatic between 1 week and 1 month, followed by
motor sub-score 37.8 (9.5) 38.6 (9.4) significant between 1 month and 3 months, and small but
cognitive sub-score 31.4 (4.2) 31.5 (4.0) not significant between 3 and 6 months after stroke,
FAC 1.4 (0.5) 0.9 (0.3) regardless of stroke severity or paralytic limbs.23 25
FMA total score 141.8 (25.8) 134.6 (29.8) Changes of FIM motor sub-score and of FAC in the pres-
motor sub-score 33.6 (23.3) 28.8 (20.9)
ent study were consistent with these findings (Fig. 2). Ben-
lower extremity 9.6 (6.3) 11.0 (5.9)
efits from the acute stroke rehabilitation within 1 month
sub-score
balance sub-score 7.1 (1.8) 6.0 (2.1) after the stroke onset, which is the dramatic recovery
mRS 4.0 (0.0) 4.0 (0.0) period, could be hard to be caught by conventional out-
Apathy scale 11.3 (9.6) 9.2 (7.5) come measures for motor impairment in the present
All values are mean values and values in parentheses are stan-
study. Furthermore, neuropsychiatric symptoms in the
dard deviation. acute phase of stroke, which is highly concomitant with
CPT, conventional physical therapy; FAC, Functional Ambula- severe disability, could place hurdles to lead better or
tion Categories; FIM, Functional Independence Measures; FMA, rapid motor recovery by the gait training using HAL in
Fugl-Meyer Assessment; HAL, Hybrid Assistive Limb; mRS, the present study. We targeted patients with severe walk-
modified Rankin Scale. ing disability as the same criteria as our previous study.7
As a result of the reference to these criteria, severity of
walking disability assessed by the FMA lower extremity
Discussion
in the present study was worse than that in the previous
There were no significant differences in walking ability study. Yet, early gait training using HAL is feasible in
or independency in patients with severe walking disabil- patients within 10 days of stroke onset. Subacute phase of
ity following stroke, who were rehabilitated using gait the stroke, when neuropsychiatric symptoms as well as
training using HAL compared with CPT initiated within dramatic recovery in the acute phase are diminished, may
10 days post-stroke. The apathy scale, one of the second- be another target to investigate the benefit from the gait
ary outcomes, showed a trend toward improvement in training using HAL.
the HAL group at the completion of gait training (2nd Apathy, which was the one of the secondary outcomes,
assessment), but this trend was less pronounced at the 3rd is characterized by a quantitative reduction of self-

Table 3A. Results of the primary and secondary outcomes, (A) Primary outcomes.

Time point HAL group CPT group Difference between two P

(n=12) (n=10) groups (95% CI)
DFIM motor sub-score 2nd 14.5 (8.8) 15.8 (9.1) -1.33 (-9.42, 6.77) 0.74
DFAC 2nd 0.8 (0.6) 1.2 (1.0) -0.289 (-1.17, 0.593) 0.50
Except for difference between two groups and P, values are mean values and values in parentheses are standard deviation.
D, changes from baseline; CI, confidence interval; CPT, conventional physical therapy; FAC, Functional Ambulation Categories; FIM,
Functional Independence Measures; HAL, Hybrid Assistive Limb

Table 3B. Results of the primary and secondary outcomes, (B) Secondary outcomes.

Time point HAL group (n=12) CPT group (n=10)

DFIM total score MP 8.3 (3.25, 13.3) 14.1 (7.74, 20.5)
2nd 15.3 (8.94, 21.7) 17.6 (11.1, 24.1)
3rd 41.9 (36.0, 47.8) 41.6 (37.2, 46.0)
DFMA total score 2nd 22.3 (16.3, 28.4) 16.1 (9.52, 22.7)
3rd 42.8 (28.2, 57.3) 45.5 (30.8, 60.2)
DmRS 2nd -0.4 (-0.744, -0.0895) -0.4 (-1.09, 0.291)
3rd -1.3 (-1.96, -0.708) -1.2 (-2.01, -0.388)
DApathy scale 2nd -3.8 (-8.14, 0.475) 1.2 (-2.66, 5.06)
3rd -1.0 (-6.48, 4.48) 0.7 (-3.35, 4.75)
All values are mean values and values in parentheses are 95% confidence interval.
D, changes from baseline; CPT, conventional physical therapy; FIM, Functional Independence Measures; FMA, Fugl-Meyer Assessment;
HAL, Hybrid Assistive Limb; MP, mid-point (completion of 10 sessions of gait training); mRS, modified Rankin Scale.
6 C. YOKOTA ET AL.

Fig. 2. (A) Time course of DFIM motor sub-score. Mean values are plotted for baseline, mid-point, second, and third assessment time points. Error bars represent
standard deviation. There were no significant differences between HAL and CPT groups at any time point. (B) Time course of DFAC. Mean values are plotted for
baseline, second, and third assessment time points. Error bars represent standard deviation. There were no significant differences between HAL and CPT groups
at any time point.
D, changes from baseline; CPT, conventional physical therapy; FAC, Functional Ambulation Category; FIM, Functional Independence Measure;
HAL, Hybrid Assistive Limb; MP, mid-point (completion of 10 sessions of gait training)

generated voluntary and goal-directed behavior.26 In the
HAL group, the apathy scale at the second assessment
decreased from baseline. HAL has an interactive biofeed-
back mechanism, which allows the wearer to easily com-
municate their intentions with HAL.17 In brief, the
interactive neural loop starting from the brain and return-
ing to the brain through proprioception as bioelectrical
signals from the limbs enables a wearer’s small voluntary
movements to accomplish the intended actions.27,28 The
attainment of the intended movement by that interactive
biofeedback would facilitate the wearer’s motivation to
conduct gait rehabilitation. Continuous gait rehabilitation
using HAL for longer period than 20 sessions of the pres-
ent study may lead the improvement of the walking abil-
ity as well as apathetic symptom.
The present study has a few limitations that need to
be addressed. First, although the randomized con-
trolled method provided important evidence by
focusing on the outcome measures reported in the pre-
vious study, 7 it is difficult to generalize due to the small
sample size and the fact that this was a single-center
study. Second, the physical therapists were not blinded
when conducting the assessments. However, the meas-
urements were performed in the same training room
and in the same way to avoid inter-rater differences or
evaluation bias.
In conclusion, compared with conventional physical
therapy, early gait training using HAL (established within
10 days after stroke onset) did not significantly improve
the walking ability and independence of patients with
acute stroke with severe walking disability. Apathy scale
decreased at the completion of the gait training using
HAL, suggesting that the gait training using HAL could
ameliorate the apathetic state after stroke. No adverse
events were observed in the HAL group. Additional mul-
ticenter, randomized studies of robot-assisted
EFFECT OF CYBORG-TYPE ROBOT HYBRID ASSISTIVE LIMB
rehabilitation for patients with stroke are required to
determine the optimal timing to initiate gait training, ideal
frequencies of HAL exercise, and outcome measures,
including neuropsychiatric symptoms.
Funding
This study was supported by the Intramural Research
Fund of the National Cerebral and Cardiovascular Center
(21-1-4) and Cyberdyne Inc Japan (#C677).
Declaration of Competing Interest
Yoshiyuki Sankai declares conflict of interest using a
standard form. The other authors have none of declara-
tions of interest.
Acknowledgments: We are deeply grateful to Dr. Toshi-
mitsu Hamasaki for his statistical advice for our study.
Supplementary materials
Supplementary material associated with this article can
be found, in the online version, at doi:10.1016/j.jstrokecer
ebrovasdis.2023.107020.
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