Neurorehabilitation for Stroke Patients with Hemiparesis ...

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

https://creativecommons.org/licenses/by/4.0/

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


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


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


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:


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.


31

Neurorehabilitation for Stroke Patients with Hemiparesis ...

Documents