Neurorehabilitation for Stroke Patients with Hemiparesis
Functional Recovery and Motor Learning
KAORU HONAGA*
*Department of Rehabilitation Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan
Stroke is a disease that leads to long-term disability, with about 80% of stroke patients having upper extremity
paresis just after stroke and more than 40% in the chronic phase. The functional prognosis of the paretic upper
extremity is dependent on its severity, and for severe paresis, it is difficult to obtain the function for practical use of
daily living. Therefore, symptomatic approaches such as effective utilization of residual functions and
compensation by the unaffected side, including dominant hand exchange training, self-help devices, and
environment setting after accepting the state of paresis, are adopted in the conventional rehabilitation adjuvant
approaches for paretic upper extremity. Neurorehabilitation techniques have been developed to modulate cortical
excitability and improve paretic upper extremity function. The main concept of the newly developed
neurorehabilitation techniques is task-oriented training and dose dependent plasticity. Constraint-induced
movement therapy is an intensive training of the paretic upper extremity in which patients use their paretic upper
extremity with their unaffected hand constrained and overcome learned non-use. Neuromuscular electrical
stimulation is usually performed along with other rehabilitation approaches. Stimulation of the target nerve assists
the movement of the paretic upper extremity and reduces the difficulty of the task. Non-invasive brain
stimulation, such as repetitive transcranial magnetic stimulation and transcranial direct current stimulation, could
temporarily modulate cortical excitability by preconditioning before rehabilitation and is usually performed before
conventional rehabilitation. Robotics is used to assist the patientʼs performance like a neuromuscular electrical
stimulation. These new rehabilitation techniques are combined and used as a hybrid rehabilitation therapy. The
tailor-made neurorehabilitation approaches adjusted to the paresis and needs of individual patients are needed for
functional recovery.
Key words: cortical plasticity, constraint-induced movement therapy (CI therapy), non-invasive brain
stimulation, robotics
Introduction
Stroke is a disease that leads to long-term
disability. The common deficit after stroke is
hemiparesis of the contralateral upper limb, with
about 80% of stroke patients having upper extrem-
ity paresis just after stroke and more than 40%
having it in the chronic phase 1). The impairments of
the upper extremity include muscle weakness,
change of muscle tone, contracture, sensory weak-
ness, and loss of dexterity. These impairments due
to stroke are a significant inhibitor of daily living. In
particular, hand function, such as pinching, grasp-
ing, and gripping, is an important function of self-
care activities. Patients with severe hemiparesis
must use their unaffected hand to compensate for
their affected hand.
The recovery of the paretic upper extremity
24
Special Reviews
Juntendo Medical Journal2021. 67(1), 24-31
Kaoru Honaga(ORCID iD: https://orcid.org/0000-0003-0885-2876)
Department of Rehabilitation Medicine, Juntendo University Graduate School of Medicine
2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
TEL: +81-3-3813-3111 FAX: +81-3-5684-1861 E-mail: [email protected]
350th Triannual Meeting of the Juntendo Medical Society: Forefronts of Rehabilitation Medicine〔Held on Sep. 10, 2020〕
〔Received Nov. 28, 2020〕〔Accepted Dec. 26, 2020〕
Copyright © 2021 The JuntendoMedical Society. This is an open access article distributed under the terms of Creative Commons Attribution Li-
cense (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original source is properly credited.
doi: 10.14789/jmj.2021.67.JMJ20-R22
depends on the severity of paresis. Patients with
mild to moderate upper extremity paresis in the
acute phase have a good prognosis for functional
recovery, with 71% of these patients achieving at
least some dexterity at six months after stroke 2).
However, the prognosis in severely affected
patients is poor, with about 60% failing to achieve
some dexterity at six months after stroke 3). Finally,
only 5% of patients who initially experienced
complete paralysis achieve functional use of their
upper extremities. Upper extremity impairments
chronically affect functional independence and
satisfaction in 5070% of all stroke patients 4).
Furthermore, the recovery of the paretic upper
extremity begins within a few weeks after onset of
stroke, and the prognosis of functional outcome is
poor if there is no measurable grip strength one
month after stroke 5).
It has been suggested that 95% of recovery in the
paretic upper extremity is completed by 1115
weeks after onset of stroke 6); however, it is difficult
to predict the function recovery of the paretic
extremity in patients with chronic stroke. There-
fore, the aim of rehabilitation for patients with
severe hemiparesis is learning how to perform their
activities of daily living only with their unaffected
extremities.
Historically, it has been suggested that regenera-
tion of the central nervous system damaged by
stroke is difficult. However, with the progress of
neuroscience, the mechanisms of neurogenesis
(regeneration) 7) and synaptic plasticity 8) has been
studied in the last 20 years, and the field of
neurorehabilitation has developed rapidly. The
scientific evidence of newly developed stroke
rehabilitation approaches has been discussed. The
purpose of this review is to discuss the mechanism
of brain plasticity and newly developed rehabilita-
tion approaches, especially for the paresis of the
upper extremity after stroke.
Brain plasticity
Brain plasticity allows the cerebral cortex to
adapt to a new environment and promotes tissue
reorganization if the brain is injured by trauma or
external environmental changes (such as infarc-
tion).
Immediately after stroke, the region deprived of
blood supply undergoes cell death, leading to brain
atrophy in the affected region. Areas around the
infarction, which also experience reduced blood
supply (penumbra), are also at risk of cell death,
but structure and function can be preserved or
recovered when reperfusion occurs 9). Furthermore,
the area near the lesion undergoes functional as
well as structural reorganization with recovery; it
has been shown to undergo a period of increased
axonal sprouting and neurogenesis, with a rise in
migration of immature neurons 10).
Motor recovery can occur following stroke, either
through spontaneous recovery or rehabilitation.
Animal studies providing initial evidence that both
functional and structural brain reorganization
occurs after localized infarctions have highlighted
the importance of post-injury training 8). In particu-
lar, task-specific training post infarction induces
synaptogenesis, dendritic branching and growth,
and formation of new long-range connections; all of
which may be conducive for post-injury plasticity.
In non-human primates, reorganization of motor
function in the spared cortical territory, not only
adjacent to but also remote from the damaged
cortex, can occur both spontaneously and in
response to rehabilitation. Similar to that of non-
human primates, the injured human brain seems to
go through a process of reorganization poststroke,
and adaptive brain changes appear to be related to
motor training and rehabilitation, leading to
improved functional outcomes. Identifying struc-
tural changes associated with functional recovery
could inform tailored rehabilitation approaches to
optimally boost adaptive brain changes.
Newly developed rehabilitation approaches for
upper extremity
The guidelines of the American Stroke Associa-
tion recommend functional task training, activities
of daily living training tailored to individual needs
and instrumental activities of daily living training as
a class Ⅰ recommendation (should be performed),
and constraint-induced movement therapy, robotic
therapy, neuromuscular electrical stimulation, men-
tal practice, strengthening exercises, and virtual
reality training as a class II recommendation for
upper extremity activity 11). However, the practical
use of severe paretic upper extremity is difficult,
Juntendo Medical Journal 67(1), 2021
25
and there is insufficient evidence supporting its
utility, especially for the hand 12). This is because it is
difficult to perform task-specific training suffi-
ciently if the patients have severe hemiparesis. The
consensus on rehabilitation of the paretic hand is to
ensure a positive functional outcome; rehabilitation
programs are based on task-oriented repetitive
training 13). Many newly developed rehabilitation
approaches aim to enhance the function of the
paretic upper extremity and assist in performing
task-oriented rehabilitation.
Constraint-induced movement therapy
Constraint-induced movement therapy (CI ther-
apy) is a representative approach of neurorehabili-
tation for paresis of the upper extremity. In CI
therapy, the unaffected upper extremity of the
patients is restrained, and it aims to improve upper
extremity function by intensive and stepwise
training 14).
Taub et al. 15) explained that patients with severe
hemiparesis do not use their paretic upper extrem-
ity based on the concept of learned non-use. In
addition to the paresis itself, the affected upper
extremity has learned non-use because of the
difficulty associated with its usage. In CI therapy,
the use of the paretic upper extremity for activities
of daily living is increased by restraining the
unaffected upper extremity and forcing the paretic
upper extremity to perform a shaping task. This
approach provides positive reinforcement, changes
motivation, and helps the extremity to overcome
learned non-use by utilizing plasticity of the brain.
CI therapy does not require any special devices
and can be performed at any hospital with a trained
rehabilitation doctor and an occupational therapist;
this has already been confirmed by large-scale
clinical trials 16) 17).
The main components of CI therapy are the
following: 1) repetitive task-oriented training,
2) strategies to reflect the functional improvement
acquired by practice into real life (Transfer
package), and 3) constraining the use of the
unaffected upper-extremity 18).
Wolff compared the effects of CI therapy between
a group that received CI therapy 39 months after
stroke onset (early group) and a group that
received it 1521 months after stroke onset
(delayed group), and there was a significant
improvement in paretic upper extremity function in
the early group compared to that in the delayed
group 19).
Moreover, there are the possibilities that the
functional recovery of the paretic upper extremity
could be promoted by performing CI therapy
during the convalescent rehabilitation period.
However, clinical applicability of standard CI
therapy 14) is limited as it is time consuming and
expensive owing to the need for trained personnel;
therefore, CI therapy with a modified protocol
according to each facility has been developed. In
some modified CI therapies, constraining the
unaffected upper extremity is not necessary 20).
CI therapy and its modifications are easy to
combine with other rehabilitation approaches. In
recent years, the number of practical reports 21) 22) of
combination therapy with various neurorehabilita-
tion approaches has increased rapidly, and the
range of indications for CI therapy has expanded.
Neuromuscular electrical stimulation
Electrical stimulation of peripheral nerves and
muscles has been traditionally performed for a long
time in many fields of rehabilitation. Depending on
the purpose of electrical stimulation, electrical
stimulation therapy was divided into the following
types: 1) transcutaneous electrical nerve stimula-
tion (TENS) for reduction of pain, 2) therapeutic
electrical stimulation (TES) for strengthening
muscles, improving edemas, suppressing spasticity,
healing wounds, and promoting blood flow, and
3) functional electrical stimulation (FES) for func-
tional recovery by controlling the nerves and
paretic muscles.
For hemiparesis after stroke, TES has been
widely used to reduce spasticity and strengthen
muscle strength. However, in recent years, with the
development of neurorehabilitation, FES has spread
rapidly. The practical application of FES is often
reported as neuromuscular electrical stimulation
(NMES). The target of NMES is the lower motor
neuron that controls the paretic muscle, and muscle
contraction is induced by depolarizing the mem-
brane potential of the innervating nerve of the
target muscle or the muscle itself by NMES.
Parameters that must be considered in general
Honaga K: Neurorehabilitation for stroke patients with hemiparesis - functional recovery and motor learning
26
NMES rehabilitation include frequency, pulse width/
duration, stimulation intensity, and duty cycle 23)
(Figure-1).
The mechanism of NMES for nerves and muscles
has not been completely clarified, but both central
and peripheral theories have been suggested. It has
been hypothesized that NMES promotes motor re-
learning by increasing synaptic transmission effi-
ciency. Kanash et al. reported that a 25-Hz NMES of
the common peroneal nerve with an intensity above
the motor threshold for 30 min changed neurotrans-
mission at the cortical level, resulting in increasing
motor evoked potential (MEP) of the tibialis
anterior muscle. Furthermore, the effect lasted for
at least 30 min after the end of the stimulation 24).
It has also been reported that the central effects
of NMES are enhanced by combining voluntary
movements with stimulation. Khaslavskiaia et al.
reported that 30-min low-frequency repetitive
electrical stimulation of the tibialis anterior muscle
of the lower extremities in healthy adults resulted
in a stronger change in MEP amplitude with the
combination of voluntary movement and electrical
stimulation compared to those with voluntary
movement and electrical stimulation alone 25). The
mechanism of NMES for peripheral nerves is
thought to include increasing muscle mass and
output, reducing spasticity, and improving fatigue
tolerance 26).
Practical approaches of NMES for stroke patients
include cyclic NMES, which stimulates target
muscles during a certain period to promote passive
muscle contraction, biofeedback NMES that stimu-
lates the target muscle at the timing of paretic
muscle activity, and neuroprostheses using devices
that include the FES system27).
The biofeedback NMES approach is usually
combined with a conventional surface electromyog-
raphy biofeedback system. This system is easy to
combine with other rehabilitation approaches. The
effect of NMES alone is not efficient; therefore,
NMES is usually used with a combination of other
neurorehabilitation approaches as a hybrid therapy.
There are a variety of rehabilitation procedures
performed in combination with NMES, including
mirror therapy, repetitive cranial porcelain stimula-
tion therapy, CI therapy, robot rehabilitation, and
image training 26) 28).
Therefore, the rehabilitation strategy of NMES is
that, under the support of NMES, patients perform
specific tasks that they could not do without the
repeated assistance of NMES, and then these active
trainings promote functional recovery.
Non-invasive brain stimulation
Transcranial magnetic stimulation (TMS) and
transcranial direct current stimulation (tDCS) can
stimulate the brain cortex without injury and are
known as non-invasive brain stimulation (NIBS)
techniques.
The basic strategy of neurorehabilitation with
NIBS is to enhance the affected hemisphere or
suppress the unaffected hemisphere (Figure-2).
After stroke onset, it is suggested that the
excitability of the affected hemisphere, including in
the lesion, is decreased and the excitability of the
unaffected hemisphere is enhanced, and that the
Juntendo Medical Journal 67(1), 2021
27
① ①
②②
③③
1:2(Duty cycle)
①Pulse duration(us)②Stimulus intensity(mA)③frequency(Hz)
Square wave Sine wave
Figure-1 Parameters of neuromuscular electrical stimulation
imbalance between both hemispheres affects the
paresis 29). Repetitive TMS (rTMS) to the brain
cortex could change the excitability of the cortex
depending on the frequency of stimulation. rTMS
can increase the excitability of corticospinal neu-
rons directly (suprathreshold >5 Hz rTMS: high-
frequency rTMS) or decrease excitability through
cortical interneurons projecting to corticospinal
cells (suprathreshold low-frequency rTMS) 30).
Apart from conventional rTMS (low-frequency
and high-frequency rTMS), new TMS approaches,
such as theta burst stimulation (TBS), paired
associative stimulation (PAS), and TMS condition-
ing, promote brain modulation.
TBS includes three pulses of stimulation at 50 Hz,
repeated every 200 ms. In the intermittent TBS
pattern (iTBS), a 2 s train of TBS is repeated every
10 s for a total of 190 s (600 pulses). In the
intermediate TBS paradigm (imTBS), a 5 s train of
TBS is repeated every 15 s for a total of 110 s (600
pulses). In the continuous TBS paradigm (cTBS), a
40 s train of uninterrupted TBS is given (600
pulses). iTBS and cTBS are subthreshold rTMS
paradigms (i.e., the stimulator delivers an intensity
below the one needed to evoke the MEP); iTBS
increases and cTBS decreases corticospinal
excitability 31).
PAS is a TMS approach that stimulates the
cortex with simultaneous peripheral nerve
stimulation 32). Conditioning rTMS is suggested to
induce selective brain plasticity by performing
rTMS in accordance with voluntary movements 33).
The tDCS delivers a low-intensity constant
direct current through the scalp to the brain and
exerts polarity-specific modulation of corticospinal
excitability. Anodal tDCS enhances cortex excitabil-
ity, and cathodal tDCS decreases cortex
excitability 34).
Similar to that of NMES, the effect of NIBS alone
is not efficient; therefore, NIBS is usually per-
formed in combination with other neurorehabilita-
tion methods as a hybrid therapy 35).
In recent years, it has been suggested that the
excitability of the unaffected hemisphere does not
always increase and does not correlate with the
severity of paresis 36). Furthermore, the cortical
response to rTMS and tDCS is different in each
patient 37)38). Therefore, it is necessary to assess the
excitability of the stimulation site and responsive-
ness before NIBS treatment.
Botulinum toxin injection therapy
Botulinum toxin infection therapy (BTX) is a
commonly used for treating spasticity after stroke.
BTX itself cannot not improve paretic upper
extremity function. However, reducing spasticity
sometimes makes it easy for patients to perform
hand rehabilitation. Therefore, as a pre-condition-
ing therapy before rehabilitation, BTX is performed
Honaga K: Neurorehabilitation for stroke patients with hemiparesis - functional recovery and motor learning
28
LesionLesion
Interhemisphericinhibition
Anodal tDCS Cathodal tDCS
High frequent rTMS Low frequent rTMS
Figure-2 Intervention strategy of non-invasive brain stimulation (NIBS)The main strategy of NIBS is to enhance the excitability of the affected hemisphere (high-frequency
repetitive transcranial magnetic stimulation [rTMS] and or anodal transcranial direct current stimulation
[tDCS]) or suppress the excitability of the unaffected hemisphere (low-frequency rTMS or cathodal tDCS).
in patients with spasticity (Figure-3).
BTX has several benefits including improvement
of motion, suppression of contracture and spasticity,
assistance for practical usage, and enhancement of
the effect of other rehabilitation approaches by
suppressing spasticity. BTX is frequently per-
formed before other neurorehabilitation techniques,
such as CI therapy, NMES, NIBS, and robotics 21).
Robotics
The VA ROBOTICS study, a large-scale multi-
center study, confirmed that robotic upper limb
therapy is a useful and qualified approach for
stroke. A comparison of these studies showed that
upper limb robotic treatment is more effective than
traditional rehabilitation treatment 39). These
reports demonstrated that robotic rehabilitation
has a wider indication than conventional rehabilita-
tion, especially for severe hemiparesis. Other
studies have also shown that the combination of
robotic rehabilitation and conventional rehabilita-
tion approaches is more effective than conventional
rehabilitation alone or robotic rehabilitation alone at
any time after stroke 40).
There are two types of rehabilitation robots: the
exoskeleton type, which accurately controls the
kinematics of each joint, and the end-effector type,
which controls only the distal part of the affected
upper extremity 41). According to a systematic
review of 44 RCTs, which included 1,362 patients
who underwent robotic rehabilitation for paretic
upper extremity, improvement of motor function
was observed in the whole upper extremity,
shoulder, and elbow joint 42). Additionally, in the
analysis by robot type, it was found that the robot
rehabilitation for the shoulder and elbow joints,
elbow and wrist joints were more effective, and the
end-effector type was more effective than the
exoskeleton type. Therefore, the effect of robotic
rehabilitation on the paretic hand function is not
sufficient; this is a problem to be solved in the
future.
The advantage of robotic rehabilitation is that
patients can perform various tasks repeatedly,
accurately, safely, and sufficiently, and it is
expected to have a functional effect compared to
conventional rehabilitation.
Conclusion
Many clinical approaches and devices are cur-
rently available to improve motor function of the
upper extremities in stroke patients. Furthermore,
some approaches can be combined to achieve
maximum motor recovery.
However, it should be noted that there are
limitations. Most importantly, even if paralysis is
severe, patients need to use the paretic upper
extremity during daily life activities also and not
Juntendo Medical Journal 67(1), 2021
29
Figure-3 Botulinum injection therapy for the spasticityA. Stroke patient with severe spasticity of finger flexor. Spasticity inhibits the active
movement of the patientʼs hand. B. Four weeks after botulinum injection therapy, the
spasticity of finger flexor is decreased, and the patient could move his hand easily.
A B
only during rehabilitation training 43). Without
improving utility in daily life, these neurorehabilita-
tion approaches have little effect, and the effect of
rehabilitation remains temporary. We should not
only aim to improve the score of clinical dysfunction
but also to improve the function of the paretic upper
extremity in real life.
Conflict of interest statement
The author declares no competing interest.
Reference
1) Cramer SC, Nelles G, Benson RR, et al: A functional MRIstudy of subjects recovered from hemiparetic stroke.Stroke, 1997; 28: 2518-2527.
2) Nijland RH, van Wegen EE, Harmeling-van der Wel BC,Kwakkel G; EPOS Investigators: Presence of fingerextension and shoulder abduction within 72 hours afterstroke predicts functional recovery: early prediction offunctional outcome after stroke: the EPOS cohort study.Stroke, 2010; 41: 745-750.
3) Kwakkel G, Kollen BJ, van der Grond J, Prevo AJ:Probability of regaining dexterity in the flaccid upperlimb: impact of severity of paresis and time since onsetin acute stroke. Stroke, 2003; 34: 2181-2186.
4) Bonita R, Beaglehole R: Recovery of motor function afterstroke. Stroke, 1988; 19: 1497-1500.
5) Bard G, Hirschberg GG: Recovery of voluntary motionin upper extremity following hemiplegia. Arch PhysMed Rehabil, 1965; 46: 567-572.
6) Nakayama H, Jørgensen HS, Raaschou HO, Olsen TS:Recovery of upper extremity function in stroke patients:the Copenhagen Stroke Study. Arch Phys Med Rehabil,1994; 75: 394-398.
7) Eriksson PS, Perfilieva E, Björk-Eriksson T, et al:Neurogenesis in the adult human hippocampus. NatMed, 1998; 4: 1313-1317.
8) Nudo RJ, Wise BM, SiFuentes F, Milliken GW: Neuralsubstrates for the effects of rehabilitative training onmotor recovery after ischemic infarct. Science, 1996;272: 1791-1794.
9) Zhang S, Boyd J, Delaney K, Murphy TH: Rapidreversible changes in dendritic spine structure in vivogated by the degree of ischemia. J Neurosci, 2005; 25:5333-5338.
10) Carmichael ST: Cellular and molecular mechanisms ofneural repair after stroke: making waves. Ann Neurol,2006; 59: 735-742.
11) Winstein CJ, Stein J, Arena R, et al; American HeartAssociation Stroke Council, Council on Cardiovascularand Stroke Nursing, Council on Clinical Cardiology, andCouncil on Quality of Care and Outcomes Research:Guidelines for adult stroke rehabilitation and recovery:A guideline for healthcare professionals from theAmerican Heart Association/American Stroke Associa-tion. Stroke, 2016; 47: e98-e169.
12) Langhorne P, Bernhardt J, Kwakkel G: Stroke rehabili-tation. Lancet, 2011; 377: 1693-1702.
13) Oujamaa L, Relave I, Froger J, Mottet D, Pelissier JY:Rehabilitation of arm function after stroke. Literaturereview. Ann Phys Rehabil Med, 2009; 52: 269-293.
14) Taub E, Miller NE, Novack TA, et al: Technique toimprove chronic motor deficit after stroke. Arch PhysMed Rehabil, 1993; 74: 347-354.
15) Taub E, Uswatte G, Elbert T: New treatments inneurorehabilitation founded on basic research. Nat RevNeurosci, 2002; 3: 228-236.
16) Langhome P, Coupar F, Pollock A: Motor recovery afterstroke: a systematic review. Lancet Neurol, 2009; 8:741-754.
17) Wolf SL, Winstein CJ, Miller JP, et al; EXCITEInvestigators: Effect of constraint-induced movementtherapy on upper extremity function 3 to 9 months afterstroke: the EXCITE randomized clinical trial. JAMA,2006; 296: 2095-2104.
18) Morris DM, Taub E, Mark VW: Constraint-inducedmovement therapy: characterizing the interventionprotocol. Eura Medicophys, 2006; 42: 257-268.
19) Wolf SL, Thompson PA, Winstein CJ, et al: The EXCITEstroke trial: comparing early and delayed constraint-induced movement therapy. Stroke, 2010; 41: 2309-2315.
20) Brogårdh C, Lexell J: A 1-year follow-up after short-ened Constraint-induced movement therapy with andwithout Mitt poststroke. Arch Phys Med Rehabil, 2010;91: 460-464.
21) Takebayashi T, Amano S, Hanada K, et al: Therapeuticsynergism in the treatment of post-stroke arm paresisutilizing botulinum toxin, robotic therapy, and con-straint-induced movement therapy. PM R, 2014; 6:1054-1058.
22) Bolognini N, Vallar G, Casati C, et al: Neurophysiologicaland behavioral effects of tDCS combined with con-straint-induced movement therapy in poststrokepatients. Neurorehabil Neural Repair, 2011; 25: 819-829.
23) Doucet BM, Lam A, Griffin L: Neuromuscular electricalstimulation for skeletal muscle function. Yale J Biol Med,2012; 85: 201-215.
24) Knash ME, Kido A, Gorassini M, Chan KM, Stein RB:Electrical stimulation of the human common peronealnerve elicits lasting facilitation of cortical motor-evokedpotentials. Exp Brain Res, 2003; 153: 366-377.
25) Khaslavskaia S, Sinkjaer T: Motor cortex excitabilityfollowing repetitive electrical stimulation of the commonperoneal nerve depends on the voluntary drive. ExpBrain Res, 2005; 162: 497-502.
26) Knutson JS, Fu MJ, Sheffler LR, Chae J: Neuromuscularelectrical stimulation for motor restoration in hemiple-gia. Phys Med Rehabil Clin N Am, 2015; 26: 729-745.
27) Sheffler LR, Chae J: Neuromuscular electrical stimula-tion in neurorehabilitation. Muscle Nerve, 2007; 35: 562-590.
28) Fujiwara T, Kasashima Y, Honaga K, et al: Motorimprovement and corticospinal modulation induced byhybrid assistive neuromuscular dynamic stimulation(HANDS) therapy in patients with chronic stroke.Neurorehabil Neural Repair, 2009; 23: 125-132.
29) Di Pino G, Pellegrino G, Assenza G, et al: Modulation ofbrain plasticity in stroke: a novel model for neurorehabi-litation. Nat Rev Neurol, 2014; 10: 597-608.
30) Fitzgerald PB, Fountain S, Daskalakis ZJ: A comprehen-sive review of the effects of rTMS on motor corticalexcitability and inhibition. Clin Neurophysiol, 2006; 117:
Honaga K: Neurorehabilitation for stroke patients with hemiparesis - functional recovery and motor learning
30
2584-2596.31) Huang YZ, Edwards MJ, Rounis E, Bhatia KP, Rothwell
JC: Theta burst stimulation of the human motor cortex.Neuron, 2005; 45: 201-206.
32) Tsuji T, Rothwell JC: Long lasting effects of rTMS andassociated peripheral sensory input on MEPs, SEPs andtranscortical reflex excitability in humans. J Physiol,2002; 540 (Pt 1): 367-376.
33) Fujiwara T, Rothwell JC: The after effects of motorcortex rTMS depend on the state of contraction whenrTMS is applied. Clin Neurophysiol, 2004; 115: 1514-1518.
34) Nitsche MA, Paulus W: Excitability changes induced inthe human motor cortex by weak transcranial directcurrent stimulation. J Physiol, 2000; 527 (Pt 3): 633-639.
35) Hesse S, Werner C, Schonhardt EM, Bardeleben A,Jenrich W, Kirker SG: Combined transcranial directcurrent stimulation and robot-assisted arm training insubacute stroke patients: a pilot study. Restor NeurolNeurosci, 2007; 25: 9-15.
36) Honaga K, Fujiwara T, Tsuji T, Hase K, Ushiba J, Liu M:State of intracortical inhibitory interneuron activity inpatients with chronic stroke. Clin Neurophysiol, 2013;124: 364-370.
37) López-Alonso V, Cheeran B, Río-Rodríguez D, Fernán-
dez-Del-Olmo M: Inter-individual variability inresponse to non-invasive brain stimulation paradigms.Brain Stimul, 2014; 7: 372-380.
38) Wiethoff S, Hamada M, Rothwell JC: Variability inresponse to transcranial direct current stimulation of themotor cortex. Brain Stimul, 2014; 7: 468-475.
39) Wu X, Guarino P, Lo AC, Peduzzi P, Wininger M: Long-term effectiveness of intensive therapy in chronicstroke. Neurorehabil Neural Repair, 2016; 30: 583-590.
40) Bertani R, Melegari C, De Cola MC, Bramanti A,Bramanti P, Calabrò RS: Effects of robot-assisted upperlimb rehabilitation in stroke patients: a systematicreview with meta-analysis. Neurol Sci, 2017; 38: 1561-1569.
41) Molteni F, Gasperini G, Cannaviello G, Guanziroli E:Exoskeleton and end-effector robots for upper andlower limbs rehabilitation: narrative review. PM R, 2018;10 (Supplement 2): S174-S188.
42) Veerbeek JM, Langbroek-Amersfoort AC, van WegenEEH, et al: Effects of robot-assisted therapy for theupper limb after stroke. Neurorehabil Neural Repair,2017; 31: 107-121.
43) Han CE, Arbib MA, Schweighofer N: Stroke rehabilita-tion reaches a threshold. PLoS Comput Biol, 2008; 4:e1000133.
Juntendo Medical Journal 67(1), 2021
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