Application of noninvasive brain stimulation for post-stroke dysphagia rehabilitation

Application of noninvasive brain stimulation for post stroke dysphagia rehabilitation + MODEL Kaohsiung Journal of Medical Sciences (2016) xx, 1e7 Available online at www sciencedirect com ScienceDire[.]

REVIEW ARTICLE

Application of noninvasive brain stimulation

for post-stroke dysphagia rehabilitation

Zhuo Wanga, Wei-Qun Songa, Liang Wangb,*

a

Department of Rehabilitation, Xuanwu Hospital, Capital Medical University, Beijing, China

b

Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing,

China

Received 14 July 2016; accepted 9 November 2016

KEYWORDS

Dysphagia;

Noninvasive brain

stimulation;

Stroke;

Swallowing

rehabilitation

stimulation (TMS), transcranial direct-current stimulation (tDCS), as well as paired associative stimulation (PAS), has attracted increased interest and been applied experimentally in the treatment of post-stroke dysphagia (PSD) This review presented a synopsis of the current research for the application of NIBS on PSD The intention here was to understand the current research progress and limitations in this field and to stimulate potential research questions not yet investigated for the application of NIBS on patients with PSD Here we successively re-viewed advances of repetitive TMS (rTMS), tDCS, and PAS techniques on both healthy partici-pants and PSD patients in three aspects, including scientific researches about dysphagia mechanism, applied studies about stimulation parameters, and clinical trials about their ther-apeutic effects The techniques of NIBS, especially rTMS, have been used by the researchers to explore the different mechanisms between swallowing recovery and extremity rehabilitation The key findings included the important role of intact hemisphere reorganization for PSD re-covery, and the use of NIBS on the contra-lesional side as a therapeutic potential for dysphagia rehabilitation Though significant results were achieved in most studies by using NIBS on swal-lowing rehabilitation, it is still difficult to draw conclusions for the efficacy of these neurosti-mulation techniques, considering the great disparities between studies

by-nc-nd/4.0/)

Conflicts of interest: All authors declare no conflicts of interest.

* Corresponding author Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Tiantan Xili Number 6, Dongcheng District, Beijing, 100050, China.

E-mail address: saintage7@126.com (L Wang).

http://dx.doi.org/10.1016/j.kjms.2016.11.007

1607-551X/Copyright ª 2016, Kaohsiung Medical University Published by Elsevier Taiwan LLC This is an open access article under the

CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ).

Available online atwww.sciencedirect.com

ScienceDirect journal homepage: http:/ /www.kjms-onli ne.com

Dysphagia, a swallowing disorder, can be divided into

oropharyngeal dysphagia and esophageal dysphagia based

on the different stages of deglutition Oropharyngeal

dysphagia, resulting from either oropharyngeal swallowing

dysfunction or perceived difficulty in the process of

swal-lowing, is usually a manifestation of a systemic disease

rather than a disease specific to the oropharynx[1] Stroke

is a representative cause of oropharyngeal dysphagia, and

in acute stroke, the prevalence of dysphagia has been

re-ported as being between 37% and 78% [2] Post-stroke

dysphagia (PSD), which is a common medical complication

that affects many patients in the first few hours and days

after ictus, is associated with increased mortality and

morbidity, partially due to aspiration, pneumonia, and

malnutrition[3] In most patients, PSD can improve

spon-taneously; however, in approximately 11e50% of patients,

it is a long-term disability[2,3]

The primary goal of treatment for dysphagia after stroke

is to improve the amount and variety of food and liquid which

are swallowed orally while minimizing the risk of aspiration

and related complications The currently used treatment

methods for PSD include posture training, dietary

modifica-tions, swallowing exercises, drug therapy, oromotor

stimu-lation, neuromuscular electrical stimustimu-lation, botulinum

toxin injection, and noninvasive brain stimulation (NIBS)[4]

As a powerful method to modulate human brain

func-tion, NIBS commonly consists of transcranial magnetic

stimulation (TMS), transcranial direct-current stimulation

(tDCS), and paired associative stimulation (PAS) PAS is

derived by combining peripheral stimulation to the targeted

muscle with TMS or tDCS over the representational area of

that muscle in the motor cortex[5,6] The reasons why NIBS

can be utilized for the PSD rehabilitation mainly include the

following: first, PSD has been believed to be associated with

damage to the cortex and subcortical structures, including,

but not limited to, the lower motor neurons of the

swal-lowing center in the brainstem; second, cortical

re-organization, known as neuroplasticity[7], which could be

purposefully modulated by NIBS, as described below, leads

to swallowing recovery Although the application of NIBS

exhibited synergistic effects over time[4], it is still

unre-liable for proposing any specific recruitment criteria due to

the limited number of well-designed, long-term follow-up

studies Basically, the successful implementation of these

techniques as interventional strategies will rely on an

improved understanding of the underlying neuronal

corre-lates of functional recovery[6]

In this paper, we sequentially review the progress made by

utilizing TMS, tDCS, and PAS on healthy participants and PSD

patients, with the goals of investigating whether NIBS has

brought light to the mechanism research of PSD, verifying

whether the usage of NIBS on PSD rehabilitation has shown

satisfactory results, and determining whether some

meth-odological limitations remain in need of further investigation

Utilization of TMS on PSD

Approximately three decades ago, Barker et al.[8]

demon-strated that it was possible to stimulate both nerves and the

brain using external magnetic stimulation TMS then started

to be used in clinical neurology to study the central motor conduction time Depending on the stimulation parameters, TMS can excite or inhibit the brain, thus allowing the func-tional mapping of cortical regions and the creation of tran-sient functional lesions[9] Compared with single-pulse TMS, which can depolarize neurons and evoke measurable effects, trains of stimuli (repetitive TMS, rTMS) can provide novel insights into the pathophysiology of the neural circuitry, which have been widely utilized in the areas of motor and speech recovery[10] The application of TMS on dysphagia stroke can be summarized in the following three aspects

The mechanistic research of PSD using TMS

When discussing research on the mechanisms of dysphagia,

it is necessary to mention Dr Hamdy et al.[11]who were the first to use TMS on this subject They used TMS in 20 healthy participants, two decades ago, to describe the physiological characteristics of the corticofugal pathways to swallowing muscles[11] They found, for the first time, that the muscles involved in swallowing appeared to be repre-sented bilaterally on the precentral cortex, which displayed interhemispheric asymmetry, independent of handedness These findings proved that the cortex plays an important role in regulating the brainstem swallowing program

A year later, they published additional experimental results on this subject [12] To acquire cortical stimula-tions, TMS was used on 20 post-stroke patients with or without dysphagia for the first time The authors found that the PSD patients had smaller pharyngeal responses on the unaffected hemisphere than did patients who retained normal swallowing This result was consistent with their prior finding of the presence of interhemispheric asymme-try with the swallowing motor function and suggested that dysphagia after unilateral hemispheric stroke was related

to the magnitude of pharyngeal motor representation in the unaffected hemisphere

Based on these results, Hamdy et al [13] speculated that the recovery of swallowing in PSD patients could be explained by the compensatory reorganization of swallow-ing function in the intact hemisphere rather than the restoration of swallowing function in the damaged hemi-sphere, and they performed another clinical study to verify this speculation After 3 months of follow-up for 28 patients who had a unilateral hemispheric stroke, the researchers demonstrated that the cortical map representation of the pharyngeal musculature in the undamaged hemisphere increased markedly in size in the PSD patients who recov-ered swallowing, but that there was no change in patients who had persistent dysphagia or who did not have dysphagia throughout These observations verified the speculation that the recovery of PSD may be dependent on compensatory strategies of cortical reorganization, through neuroplastic changes, which can mainly be observed in the undamaged hemisphere By using the TMS technique, these findings on the mechanism of PSD and its recovery have laid the theoretical foundations for PSD rehabilitation and have facilitated further research on the neuroplasticity of the pharyngeal motor cortex in association with its functional outcome[7,14]

Studies about rTMS protocols for healthy

participants

An important issue to note concerns the experiments that

aimed to find the optimal parameters of TMS As mentioned

previously[10], a train of TMS pulses of the same intensity

applied to a single brain area at a given frequency that can

range from one stimulus per second to 20 or more is known

as rTMS It is known that the frequency and intensity of a

single TMS are associated with the disruption of cortical

function rTMS can also induce a modulation of cortical

excitability This effect may range from inhibition to

facilitation, depending on the stimulation variables

(particularly frequency of stimulation) According to Maeda

et al [15], low-frequency rTMS, which was defined by

stimulation at frequencies 1 Hz, reduced neuronal

excit-ability, whereas high-frequency rTMS, which was defined by

stimulation at frequencies 5 Hz, increased limb motor

cortical excitability

Two experiments conducted by Dr Hamdy et al.[16,17]

further investigated the relationship between the

fre-quency of rTMS and the associated excitability of the

pharyngeal cortex and verified this discrepancy for

different frequencies of rTMS on the pharyngeal cortex By

comparing the effects of a different number of pulses in

trains of 5 Hz, 250 stimulation pulses were found to be as

effective as longer 5-Hz rTMS trains (1000 pulses) at

inducing increases in cortico-bulbar motor evoked

poten-tials (MEPs) from the pharyngeal motor cortex[16]

By contrast, a 1-Hz rTMS paradigm for 10 minutes (600

pulses) at 120% of the pharyngeal threshold was able to

generate a unilateral “virtual lesion”, which can inhibit the

cortico-bulbar output from the pharyngeal motor cortex

and interfere with swallowing behavior for up to 45 minutes

[17] The development of this inhibitory pre-conditioning

protocol of rTMS in the pharyngeal motor system

facili-tated the preclinical applications of these NIBS techniques

in a controlled environment to assess the efficacy of these

interventions in a disrupted system, as described below

Clinical research of rTMS on PSD patients

Regarding the clinical utilization of rTMS on PSD patients,

well-designed clinical trials have been reported since 2009,

although they utilized different protocols, as shown in

Khedr et al.[18]reported the clinical effects of PSD with

rTMS for the first time in 2009 To increase the cortical

excitability of the lesioned hemisphere, they used a 3-Hz

rTMS on the affected hemisphere in the real group of

pa-tients with acute PSD due to monohemispheric stroke Real

rTMS led to a significantly greater improvement in dysphagia

and motor disability that was maintained over 2 months of

follow-up compared with the sham group Kim et al [19]

then compared the effect of low-frequency (1 Hz) and

high-frequency (5 Hz) rTMS on recovery of the swallowing

function in patients with a brain injury, including infarction,

hemorrhage, and brain injury It was found that inhibitory

stimulation of low-frequency rTMS on the contra-lesional

hemisphere facilitated the recovery of PSD Furthermore,

3 years later, another group from South Korea completed a T

T lesion

Study design

DOSS/BI positive

Infarct; hemorrhage;

Mylohyoid “hot

Abo-Elfetoh, 2010

Acutebrainstem infarct

DOSS/BI positive

comprehensive comparison of the effect of low-frequency

rTMS and neuromuscular electrical stimulation (NMES) on

subacute PSD[20] They used the same rTMS protocol as Kim

et al [19]and proved that both low-frequency rTMS and

NMES could induce early recovery from dysphagia It is

important to note that the goal of these three clinical trials

was either to provide excitatory stimulation over the lesion

hemisphere or to decrease the transcallosal inhibition to the

affected hemisphere by inhibitory stimulation over the

healthy side, which was consistent with the rationale behind

limb motor recovery

As mentioned previously, the mechanism of dysphagia

recovery has been proven to be different from that of limb

motor recovery, as the role of intact hemisphere

reorgani-zation is important for PSD recovery[21] Several clinical

trials have been performed to determine the therapeutic

effect of excitatory stimulation over the unaffected

pharyngeal motor cortex conducted by high-frequency

rTMS A randomized controlled trial (RCT) performed by a

study team of South Koreans was completed in 2013[22]

The experimental group received high-frequency (5 Hz)

rTMS over the contra-lesional pharyngeal motor cortex

According to their results, the prevalence rates of aspiration

and pharyngeal residue were reduced by half, which meant

that high-frequency rTMS on the contra-lesional pharyngeal

motor cortex can be viewed as a new and effective

treat-ment method for PSD patients Another RCT compared the

effect of high-frequency rTMS on the contra-lesional

pharyngeal motor cortex with two other neurostimulation

techniques [pharyngeal electrical stimulation ( PES) and

PAS][23] The results showed that the corticobulbar

excit-ability of the pharyngeal motor cortex was beneficially

modulated by PES and PAS and, to a lesser extent, by rTMS,

with functionally relevant changes in the unaffected

hemi-sphere This result further verified prior results of

mecha-nistic studies on PSD, indicating that an increase in

corticobulbar excitability in the unaffected projection was

correlated with an improvement in swallowing safety This

result also suggested that it is necessary to conduct more

detailed trials on different stimulation montages of rTMS to

determine its long-term effects on swallowing

In addition, some studies of rTMS on dysphagia

rehabili-tation caused by brainstem infarctions have been

completed Khedr et al.[18]and Khedr and Abo-Elfetoh[24]

used the same parameters of rTMS as their prior trial on 22

patients with acute brainstem stroke who had severe bulbar

manifestation The major difference from other studies was

that bilateral pharyngeal motor cortex stimulation of rTMS

was chosen for these patients As a result, active rTMS

improved dysphagia compared with sham rTMS, which meant

that rTMS could be a useful adjuvant strategy in the

neuro-rehabilitation of dysphagia due to brainstem infarction

Utilization of tDCS on PSD

As a novel, noninvasive brain stimulation technique that

delivers a small electric current continuously across the

cerebral cortex, tDCS appears to be both safe and well

tolerated, and it can directly alter excitability within the

brain for periods outlasting the duration of stimulation[25]

Research on the effects of tDCS on dysphagia was

conducted not only much later than that of rTMS but also far behind research on the use of this technique on limb motor rehabilitation

Parameters and reactions of tDCS on the healthy pharyngeal motor cortex

The first report on the application of tDCS on a human pharyngeal motor cortex was published in 2009 by Dr Hamdy et al [26].They studied the effects of differing doses of tDCS on the physiology of a healthy human pharyngeal motor cortex Both 10-minute 1.5 mA and 20-minute 1 mA anodal stimulation were found to induce in-creases in cortical excitability in the stimulated hemi-sphere They concluded that anodal tDCS can alter pharyngeal motor cortex excitability in an intensity-dependent manner with little evidence for transcallosal spread, and they speculated that the anodal stimulation of tDCS may provide a useful way of promoting recovery in dysphagic patients

In a later study, the authors paired swallowing training and sucking flavored lollipop interventions with tDCS in an undisrupted system and reported a bilateral increase in swallow-related brain activation on magnetoencephalog-raphy (MEG) after tDCS[27] This result was contradictory

to the prior study, which can, to some extent, be explained

by its newly involved task of swallowing training

Clinical applications of tDCS on PSD patients

To date, only three RCTs have been published on the effectiveness of tDCS in PSD patients, the main parameters

of which are labelled in Table 2 Similar to the clinical usage of rTMS on PSD patients, the greatest discrepancy of the experimental designs of these RCTs existed in the tar-geted hemisphere of the cortical stimulation

In the first pilot study [28], 14 patients with subacute unilateral hemispheric infarction were randomized to anodal tDCS versus sham stimulation to the motor cortical representation of swallowing in the unaffected hemisphere with concurrent standardized swallowing maneuvers The positive results verified that measures that enhance cortical input and sensorimotor control of brainstem swal-lowing may be beneficial for dysphagia recovery However, this research was criticized for using parameters that were previously untested in the pharyngeal system with limited measurable effects on swallowing behavior

A further study was reported by Dr Hamdy et al.[29] In the first step of their research and to acquire a virtual dysphagia, 1-Hz rTMS pre-conditioning to the strongest pharyngeal projection was used in 15 healthy participants utilizing the method previously mentioned[17] Next, the optimal tDCS parameters (anodal, 1.5 mA, 10 minutes) were applied contralaterally As a result, tDCS to the contralateral pharyngeal motor cortex reversed both the neurophysiological and behavioral effects of focal cortical inhibition on swallowing These results supported their prior findings that swallowing recovery was associated with neuroplastic adaptation in the unlesioned hemisphere and that tDCS on the contra-lesional side can be used as a therapeutic potential for dysphagia rehabilitation

On the contrary, two clinical trials that focused on the ipsilateral hemisphere were performed in South Korea and Japan[30,31] Both trials used evidence-based parameters (anodal, 1 mA, 20 minutes, 10 days) of tDCS to stimulate the lesioned hemisphere They achieved positive results, as ex-pected, and concluded that anodal tDCS to the ipsilesional hemisphere could significantly improve swallowing function

It is necessary to mention that the patients in the trial con-ducted by Shigematsu et al.[31]received intensive swallow-ing therapies with simultaneous brain stimulation Therefore, their results were criticized for the possible interference of simultaneous peripheral sensorimotor activities

Due to the different molecular mechanisms from rTMS, tDCS has shown little evidence for transcallosal spread[26], which indicates that the choice of the stimulation hemi-sphere is very important Based on these three clinical trials and one experiment with virtual dysphagia, it is still impossible to determine the optimal hemisphere for tDCS Further clinical studies are needed to make a direct com-parison between stimulations on the lesioned hemisphere and contra-lesional side

Utilization of PAS on PSD

The technique of PAS-induced heterosynaptic plasticity in the motor and somatosensory cortical areas is done by combining peripheral stimulation with the targeted muscle with cortical stimulations, including TMS and tDCS, over the representational area of that muscle in the motor cortex[6]

By combining these two modalities, peripheral and central, and separating them with a specific time interval, excitation

of the pharyngeal motor cortex can be strongly induced

Parameter study of PAS

It is worth noting that Dr Hamdy et al.[32], the pioneers who first introduced this technique into PSD rehabilitation, performed a series of experiments to investigate the optimal parameters The first pilot study included 15 healthy vol-unteers, and the optimal parameters and interhemispheric interactions of PAS in the bilaterally represented pharyngeal system initially were investigated[32] PAS was delivered by pairing a PES (0.2-millisecond pulse) with a single TMS pulse

on the pharyngeal motor cortex at the intensity of motor threshold plus 20% of stimulator output, and the greatest increase in cortical pharyngeal excitability was seen when the interstimulus interval was 100 milliseconds Cortical excitability in the ipsilateral hemisphere increased over 2 hours with analogous, albeit lesser, changes in the contra-lateral hemisphere The optimal duration of PAS for neuro-physiological changes was then found to be 10 minutes, according to their further study that included 12 healthy participants[5] Furthermore, by using the same parameters

as before, this study team found that participants who did not respond to an initial application of excitatory stimula-tion (PAS, 10 minutes) showed an increase in MEP responses after a repeated stimulation, which had implications for double PAS application for PSD patients who may not respond to single-dose stimulation[33]

As described in the newly published report [34], 11 healthy adults were recruited to receive real and sham PAS

DOSS P

FDS P

Shigematsu et

DOSS P

to the “stronger” motor cortex pharyngeal representation,

with an aim to investigate the specific metabolic mechanism

of PAS Following PAS, event-related functional magnetic

resonance imaging (fMRI) was performed to assess changes

in brain activation in response to swallowing and during rest

Finally, PAS was verified to induce functional alterations in

both targeted ipsilateral and contralateral areas of the

swallowing network in health Such changes highlighted the

functionality of transcallosal interactions in the swallowing

network These findings should be viewed as a complement

to the mechanism of dysphagia and its recovery and

illus-trated that PAS exerts its effects on the swallowing network

level not only on the targeted cortical motor area

Clinical study about PAS on PSD

In a pilot study of PAS on six patients with chronic and severe

dysphagic stroke, the application of PAS on the contralesional

pharyngeal motor cortex significantly increased the cortical

excitability of the unaffected hemisphere and showed

im-mediate behavioral and neurophysiological effects[5]

Based on these preclinical tests, an RCT was completed

to compare the beneficial effects of three neurostimulation

techniques, including PES, PAS, and rTMS, on chronic PSD

patients, as previously mentioned [23] The results

demonstrated that a single application of either PES or PAS

increased cortical excitability and was associated with

re-ductions in aspiration, whereas 5-Hz rTMS was less effective

when it was performed on the contra-lesional side This

result was speculated to be caused by either the different

stimulation mechanisms between PAS and rTMS or the

defective study design because a single stimulation of rTMS

was not sufficient to acquire an obvious reaction

In these experiments on healthy participants and

pa-tients, PAS was seen to induce beneficial neurophysiological

and behavioral effects in the subjects Although it is the

most promising technique, research on PAS has just started

More studies on the different stimulation choices of PAS,

including a combination of tDCS with PES, on patients with

PSD may lead to new findings in future work

Recently, there have been several trends for the

utili-zation of the NIBS techniques in the area of PSD First,

researchers have tried to combine these techniques with

new neuroradiology techniques, such as fMRI, MRS, MEG,

and even neuro-navigation systems [27,34,35] With the

advantage of neuroradiology, researchers are able to obtain

information other than behavior reactions Second, other

related cortices, such as the cerebellar cortex, have been

tested for their effects on pharyngeal cortical excitability

and swallowing responses[36,37] According to the reports

[36], high-frequency cerebellar rTMS (10 Hz) can robustly

produce physiologically relevant effects on the excitability

of frequency-specific corticobulbar projections to the

pharynx These results raise the possibility that excitatory

neurostimulation of the cerebellum may be therapeutically

useful in promoting recovery of PSD

Summary

There is no doubt that rTMS, tDCS, and PAS have been used

as powerful tools in researching the neurophysiological

mechanism of PSD; equally, there is no doubt that these techniques of NIBS will be viewed as promising methods in the hand of a rehabilitation clinician to deal with PSD in the future Given the limitations of the relevant studies, there are three issues that require further study First, although rTMS has a wider application in clinical and scientific research, more detailed comparisons about the therapeutic effects among these techniques should be performed Second, additional well-designed RCTs that have a larger sample size and long-term follow-up are needed Third, to avoid selection bias as much as possible, the targeted population of the clinical trials should be more clearly defined, and the enrolled patients with subacute or chronic dysphagia stroke should not be ambiguous

Acknowledgments

The National Natural Science Foundation of China (Grant

No 81371194) provided financial support for this study

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